ANTI psychotic drugs

• Antipsychotic drugs


  Are used primarily to treat schizophrenia, they are also effective in other psychotic and manic states, are not curative and do not eliminate chronic thought disorders, they often decrease the intensity of hallucinations and delusions, they permit the person with schizophrenia to function in a supportive environment
• Schizophrenia


  A type of chronic psychosis characterized by delusions, hallucinations and disturbances in thought, the onset of illness is often during late adolescence or early adulthood, it occurs in about 1% of the population and is a chronic and disabling disorder, it has a strong genetic component and probably reflects some fundamental developmental and biochemical abnormality
• How are Antipsychotic drugsclassified

  • First-generation: "low potency" or "high potency"
  • Second-generation
• First-generation antipsychotics


  Also called conventional drugs, are competitive inhibitors at a variety of receptors, their antipsychotic effects reflect competitive blockade of dopamine D2 receptors, more likely associated with movement disorders known as extrapyramidal symptoms (EPS), particularly drugs that bind tightly to dopaminergic neuroreceptors, such as haloperidol, movement disorders are somewhat less likely with medications that bind less potently, such as Chlorpromazine

  
• First-generation antipsychotics


  • Chlorpromazine (Thorazine), Haloperidol, Prochlorperazine (Compazine, Procomp), Haloperidol (Haldol Decanoate), Thioridazine (Mellaril)
• Second-generation antipsychotic drugs


  Also called "atypical" antipsychotics, have a lower incidence of EPS than the first-generation agents, are associated with a higher risk of metabolic adverse effects, such as diabetes, hypercholesterolemia, and weight gain, they owe their unique activity to blockade of both serotonin and dopamine receptors

  
• Second-generation antipsychotic drugs


  • Risperidone, Arpiprazole
  • Also called "atypical"

  
• Drug selection


  Second-generation agents are generally used as first-line therapy for schizophrenia to minimize the risk of debilitating EPS associated with the first-generation drugs that act primarily at the dopamine D2 receptor, the second-generation antipsychotics exhibit an efficacy that is equivalent to, and occasionally exceeds, that of the first-generation antipsychotic agents, individual patient response and comorbid conditions must often be used to guide drug selection

  
• Mechanism of action: Dopamine antagonism


  All of the first-generation and most of the second-generation antipsychotic drugs block D2 dopamine receptors in the brain and the periphery

  
• Mechanism of action: Serotonin receptor–blocking activity


  Most of the second-generation agents exert part of their action through inhibition of serotonin receptors (5-HT), particularly 5-HT2A receptors,

  
  

  Clozapine has high affinity for D1, D4, 5-HT2, muscarinic, and α-adrenergic receptors, but it is also a weak dopamine D2 receptor antagonist,

  
  

  Risperidone blocks 5-HT2Areceptors to a greater extent than it does D2 receptors, as does olanzapine,

  
  

  Aripiprazole is partial agonist at D2 and 5-HT1A receptors, as well as antagonists of 5-HT2A receptors

  
• Actions of antipsychotic drugs

  The clinical effects of antipsychotic drugs are due to a blockade at dopamine and/or serotonin receptors, many antipsychotic agents also block cholinergic, adrenergic, and histaminergic receptors, the undesirable adverse effects of antipsychotic drugs mainly result from pharmacological actions at these other receptors

  
• Antipsychotic effects


  All antipsychotic drugs can reduce hallucinations and delusions associated with schizophrenia (known as "positive" symptoms) by blocking D2 receptors in the mesolimbic system of the brain, many second-generation agents, such as clozapine, can ameliorate the negative symptoms such as blunted affect, apathy, and impaired attention, as well as cognitive impairment, to some extent

  
• Extrapyramidal effects


  Dystonias (sustained contraction of muscles leading to twisting, distorted postures), Parkinson-like symptoms, akathisia (motor restlessness), tardive dyskinesia (involuntary movements, usually of the tongue, lips, neck, trunk, and limbs) can occur with both acute and chronic treatment, blockade of dopamine receptors in the nigrostriatal pathway is believed to cause these unwanted movement symptoms, the second-generation antipsychotics exhibit a lower incidence of EPS

  
• Antiemetic effects


  The antipsychotic drugs have antiemetic effects that are mediated by blocking D2 receptors of the chemoreceptor trigger zone of the medulla

  
• Anticholinergic effects


  Some of the antipsychotics, particularly chlorpromazine, clozapine, and olanzapine, produce anticholinergic effects including blurred vision, dry mouth confusion, and inhibition of gastrointestinal and urinary tract smooth muscle, leading to constipation and urinary retention, the anticholinergic effects may actually assist in reducing the risk of EPS with these agents
• Other effects


  Blockade of α-adrenergic receptors causes orthostatic hypotension and light-headedness, in the pituitary, antipsychotics that block D2 receptors may cause an increase in prolactin release, sedation occurs with those drugs that are potent antagonists of the H1-histamine receptor, including chlorpromazine, olanzapine, quetiapine, and clozapine, sexual dysfunction, Weight gain is more significant with the second-generation agents

  
• Therapeutic uses


  1. Treatment of schizophrenia: The first-generation antipsychotics are generally most effective in treating the positive symptoms of schizophrenia, the atypical antipsychotics with 5-HT2A receptor–blocking activity may be effective in many resistant cases patients and in treating the negative symptoms of schizophrenia. 2. Prevention of nausea and vomiting: The older antipsychotics are useful in the treatment of drug-induced nausea.
• Other uses


  Chlorpromazine is used to treat intractable hiccups, Pimozide for treatment of Tourette disorder, Risperidone and aripiprazole are approved for the management of disruptive behavior and irritability secondary to autism, many antipsychotic agents are approved for the management of the manic and mixed symptoms associated with bipolar disorder, some antipsychotics like aripiprazole, is used as adjunctive agents with antidepressants for depression

  
• Absorption and metabolism

  After oral administration, the antipsychotics show variable absorption that is unaffected by food, these agents readily pass into the brain and have a large volume of distribution, they are metabolized to many different metabolites, usually by the cytochrome P-450 system in the liver, some metabolites are active and have been developed as pharmacological agents themselves, long acting injectable (LAI) formulations of antipsychotics have a therapeutic duration of action of 2 to 4 weeks, with some having a duration of 6 to 12 weeks, therefore, these LAI formulations are often used to treat outpatients and individuals who are nonadherent with oral medications
• Adverse effects: Ocular complications

  Deposits in the anterior portions of the eye (cornea and lens) are a common complication of chlorpromazine therapy, they may accentuate the normal processes of aging of the lens, thioridazine is the only antipsychotic drug that causes retinal deposits, which in advanced cases may resemble retinitis pigmentosa, the deposits are usually associated with "browning" of vision, the maximum daily dose of thioridazine has been limited to 800 mg/d to reduce the possibility of this complication
• Cautions and contraindications


  All antipsychotics may lower the seizure threshold and should be used cautiously in patients with seizure disorders or those with an increased risk for seizures, such as withdrawal from alcohol, there is increased risk for mortality when used in elderly patients with dementia-related behavioral disturbances and psychosis, antipsychotics used in patients with mood disorders should also be monitored for worsening of mood and suicidal ideation or behaviors
• Maintenance therapy followed with antipsychotic drug

  Patients who have had two or more psychotic episodes secondary to schizophrenia should receive maintenance therapy for at least 5 years, and some experts prefer indefinite therapy, the rate of relapse may be lower with second-generation drugs