ANTIPSYCHOTICS

BY P.M.EMEKA COCP-KFU

Learning Objectives
Define psychosis. How they interact with neurotransmitters. MOA, clinical uses and adverse effects. Recognize the importance of therapeutic effects produced by drugs in the treatment of mood disorders. Describe the side-effects, toxicities and druginteractions for MAO inhibitors. Discuss the roles of lithium in treatment of mood disorders.

Definition
Psychosis is a severe mental disorder in which there is extreme impairment of ability to think clearly, respond with appropriate emotion, communicate effectively, understand reality and behave appropriately.

Psychosis are among the most severe psychiatric disorders, in which there is not only marked impairment of behaviour, but also a serious inability to a. Think coherently. b. Comprehend reality. c. Gain insight into the presence of these abnormalities.

Their etiological basis Psychosis remains unknown, although generally the followings are thought to be proposed causative factors: Genetic, neurodevelopmental, and environmental factors.. Representative syndromes in this category include schizophrenia, brief psychoses, and delusional disorders. Psychotic features also occur in major mood disorders, particularly mania and severe melancholic depression. Psychotic illnesses are characterized by disordered thought processes (as inferred from illogical or highly idiosyncratic communications) with disorganized or irrational behaviour and varying degrees of altered mood that can range from excited agitation to severe emotional withdrawal.

Psychosis
The psychotic disorders include:Schizophrenia (delusions and auditory hallucinations). Manic phase of bipolar (manic-depressive) illness. Acute idiopathic psychotic illnesses. Other conditions marked by severe agitation.

Dopamine Hypothesis
1. Drugs that increase dopamine will enhance or produce positive psychotic symptoms
E.G. Cocaine, amphetamine.

2. All known antipsychotics drugs capable of treating positive psychotic symptoms block the dopamine receptors
Esp..D-2 receptors.

Management of Psychosis
It is very important to recognise and manage psychosis a first time correctly, as delay in diagnosis may adversely affect recovery. If there is an external cause like substance abuse this must be addressed. Remember that psychosis in substance abuse can be part of dual diagnosis.

Antipsychotics
All antipsychotics are considered equally effective
Rationale for determining which medication to use is based on side effect profile

Primary mechanism of action is

Postsynaptic blockade of the D-2 receptor. D2 receptor blockade in the brain is a general pharmacodynamics property of all antipsychotics, and without it a drug will not show any antipsychotic properties.

Types of Antipsychotics
1. High potency typical antipsychotics bind to the D2 receptor with high affinity. As a result they have higher risk of extrapyramidal side effects. 2. Low potency typical antipsychotics have less affinity for the D2 receptors but tend to interact with non-dopaminergic receptors resulting in more cardiotoxic and anticholinergic adverse effects including sedation, hypotension.

The Atypical Antipsychotics

They are serotonin-dopamine 2 antagonists (SDAs) They are considered atypical in the way they affect dopamine and serotonin neurotransmission in the four key dopamine pathways in the brain, which include Mesolimbic and Nigrostriatal pathways.

The Atypical Antipsychotics

The classification of atypical antipsychotics is linked essentially to their pharmacodynamic properties, which reflect their affinities for specific receptors.
a. Atypical antipsychotics with a high selectivity for serotonin 5HT2A receptors and dopamine D2 receptors (and also 1adrenoceptors) are called serotonin-dopamine antagonists (SDA). b. Drugs showing an affinity for 5-HT2A, D2 and receptors of other systems (cholinergic, histaminergic, 5-HT1A, 5HT2C and others) are designated as multi-acting receptor-targeted antipsychotics (MARTA). c. Drugs that preferentially block D2 and D3 subtypes of the D like receptors are classified as combined D2/D3 receptor antagonists. d. A final class of atypical antipsychotics are the partial dopamine receptor agonists.

Clinical Consequences of Dopaminergic D2 Blockade: Extrapyramidal movement disorders Endocrine changes Sexual dysfunction. Possible Clinical Consequences of histamine H1 Blockade: Sedation, drowsiness Weight gain Hypotension. Possible clinical consequences of alpha-1 receptor blockade: Postural hypotension Reflex tachycardia Dizziness. Possible clinical consequences of muscarinic receptor blockade: Blurred vision, Dry mouth, Sinus tachycardia, Constipation Urinary retention, Memory dysfunction.

Classification of Antipsychotics
The original classification of antipsychotics according to their chemical structure.

Phenothiazines Thioxanthenes Butyrophenones Perathiepines Diphenylpiperidines

Conventional Antipsychotic Drugs.

Phenothiazines: Chlorpromazine, Thioridazine Mesoridazine, Trifluoperazine, Fluphenazine.
Thioxanthenes: flupenthixol, Navane. Dibenzoxazepines: Clozapine Ioxapine. Butyrophenones: Haloperidol. Perathiepines: Perazine, Trifluoperazine, Trifluthepin.

Antipsychotic adverse effects

Neuroleptic Malignant Syndrome (NMS): Characterized by severe muscle rigidity, fever, altered mental status, autonomic instability, elevated WBC, CPK and lfts. Potentially fatal. Tardive Dyskinesia (TD)-involuntary muscle movements that may not resolve with drug discontinuation- risk approx. 5% per year Extrapyramidal side effects (EPS): Acute dystonia, Parkinson syndrome, Akathisia.

Neuroleptic Malignant Syndrome

An idiosyncratic, life-threatening illness associated with antipsychotic therapy. Clinical manifestations include:
hyperpyrexia autonomic instability, board-like rigidity.

Treatment involves
Immediate discontinuation of antipsychotic Hydration Maintain vital functions Use bromocriptine and dantrolene.

Atypical or Novel Antipsychotics

MARTA (Multi-acting receptor-targeted antipsychotics) Clozapine Olanzapine Quetiapine Zotepine.

SDA(Serotonin-Dopamine antagonists) Risperidone, Ziprasidone. D2, D3 selective antagonists Sulpiride Amisulpride

Clozapine
Mechanism of Action: Weak D1=D2 block. High 5-HT2 block Alpha1, Alpha 2, H1, M1 Clinical Uses: Schizophrenia, as a mood stabilizer low EPS. Side Effects: Agranulocytosis. Do not use with Carbamazepine or other bone marrow suppressors. Sedation, Dizziness, orthostatic hypotension, Hypersalivation, Weight Gain.