First-generation antipsychotics are dopamine receptor antagonists (DRA) and are known as typical antipsychotics. They include phenothiazines (trifluoperazine, perphenazine, prochlorperazine, acetophenazine, triflupromazine, mesoridazine), butyrophenones (Haloperidol), thioxanthenes (thiothixene, chlorprothixene), dibenzoxazepines (loxapine), dihydroindole (molindone), and diphenylbutylpiperidines (pimozide).
Second-generation antipsychotics are serotonin-dopamine antagonists and are also known as atypical antipsychotics. The Food and Drug Administration (FDA) has approved 12 atypical antipsychotics as of the year 2016. They are risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, lurasidone, iloperidone, cariprazine, brexpiprazole, and clozapine.
Huntington disease, Parkinson disease, Lesch-Nyhan syndrome, pervasive developmental disorder are some other conditions where antipsychotics can be used though it is not the primary drug of choice.
This is the drug of choice when the patient has failed multiple trials of standard antipsychotic therapies. Clozapine is also useful in the treatment of tardive dyskinesia. Indications for the use of clozapine include treatment-resistant mania, severe psychotic features, obsessive-compulsive disorder, pervasive developmental disorders, childhood autism, Parkinson disease, Huntington disease and suicidal patient with schizophrenia or schizoaffective disorder.
The first-generation antipsychotics work by inhibiting dopaminergic neurotransmission. They are most effective when they block about 72% of the D2 dopamine receptors in the brain. They also have noradrenergic, cholinergic, and histaminergic blocking action.
Second-generation antipsychotics work by blocking D2 dopamine receptors as well as serotonin receptor antagonist action. 5-HT2A subtype of serotonin receptor is most commonly involved.
All dopamine receptor antagonists are available and can be administered in oral form. Except for thioridazine, pimozide, and molindone, all other first-generation antipsychotics can also be given parenterally. Haloperidol and fluphenazine can be given in long-acting depot parenteral form.
These can be administered in oral or parenteral forms. Risperidone, olanzapine, aripiprazole, and paliperidone are available as extended release or long-acting injectable forms. Clozapine, asenapine, and olanzapine are available in the sublingual formulation.
First-generation antipsychotics are associated with significant extrapyramidal side effects. Anticholinergic adverse effects like dry mouth, constipation, urinary retention are common with low potency dopamine receptor antagonists like chlorpromazine, thioridazine. The action of H1 histamine block by the dopamine receptor antagonists (DRAs) causes sedation. Chlorpromazine is the most sedating while fluphenazine, haloperidol, and pimozide are less sedating. DRAs also lower seizure threshold and chlorpromazine and thioridazine are more epileptogenic than others. Haloperidol can cause abnormal heart rhythm, ventricular arrhythmia, torsades de pointes and even sudden death if injected intravenously. Other DRAs cause prolongation of OTc interval, prolonged atrial and ventricular contraction and other cardiac conduction abnormalities. Thioridazine has a black box warning for sudden cardiac death. Low-potency DRA like chlorpromazine, thioridazine commonly cause orthostatic hypotension. This adverse effect caused by alpha-adrenergic block is usually seen initially when treatment is started and patients often develop a tolerance. It is important to avoid treating the hypotension with Epinephrine. Leukopenia, thrombocytopenia and blood dyscrasia are rare side effects of treatment with DRAs. Increased serum prolactin levels along with galactorrhea, breast enlargement, amenorrhea, impotence in men and anorgasmia in women are known adverse effects due to the action of the dopamine receptor block in the tuberoinfundibular tract. Allergic dermatitis and photosensitivity can occur with chlorpromazine. Chlorpromazine is also associated with blue-gray skin discoloration and benign pigmentation of the lens and cornea. Thioridazine can cause retinal pigmentation which can continue even after the drug is discontinued.
Neuroleptic malignant syndrome is a rare but fatal adverse effect that can occur at any time during treatment with DRAs. The onset of symptoms is over 24 to 72 hours with increased temperature, severe muscular rigidity, confusion, agitation, elevation in white blood cell count, elevated creatinine phosphokinase levels, elevated liver enzymes, myoglobinuria and acute renal failure. The antipsychotic should be immediately discontinued and dantrolene 0.8 to 2.5 mg/kg every 6 hours up to 10 mg per day is the drug of choice. Adequate hydration, cooling and close monitoring of vital signs and serum electrolytes should be done. Though the risk of neuroleptic malignant syndrome is more with first-generation antipsychotics, second-generation antipsychotics are also known to cause this adverse effect.
Second-generation antipsychotics have a decreased risk of extrapyramidal side effects as compared to first-generation antipsychotics. Serotonin-dopamine antagonists (SDAs) are associated with significant weight gain and development of metabolic syndrome. The FDA recommends monitoring personal and family history of Diabetes, dyslipidemia, weight, and height, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile for all patients. Risperidone is associated with dizziness, anxiety, sedation, and extrapyramidal side effects. Paliperidone can cause temperature sensitivity to hot or cold temperatures and Qtc prolongation. Olanzapine has been associated with most frequently with weight gain, increased appetite, and somnolence. Quetiapine is the least likely to cause extrapyramidal side effects. The most common side effects of quetiapine are somnolence, orthostatic hypotension, and dizziness. Ziprasidone has almost no weight gain but can cause prolongation of QTc. Aripiprazole is the most common side effect of agitation, headache, and akathisia-like restlessness. Asenapine can cause an increase in serum prolactin levels, weight gain, and prolongation of QTc. Clozapine can cause hypersalivation, tachycardia, hypotension and anticholinergic side effects. Clozapine is unusual in that it suppresses dyskinesia. Clozapine cause agranulocytosis, leukopenia and requires monitoring of white blood cells and absolute neutrophil count. The FDA guidelines indicate monitoring absolute neutrophil count weekly for the first 6 months and if normal can be monitored every 2 weeks after that. Treatment with clozapine should be discontinued if absolute neutrophil count drops below 1000 cells per cubic millimeter or below 500 cell per cubic millimeter in those with benign ethnic neutropenia. Clozapine can also cause the rare side effect of cardiomyopathy and myocarditis.
Larger doses of all antipsychotics are associated with a higher incidence of adverse effects.
First-generation antipsychotics are contraindicated in the following situations:
Second-generation antipsychotics carry the black box warning of increased incidence of stroke in elderly patients with dementia. It is recommended to avoid the use of second-generation antipsychotics along with other drugs that prolong the QTc interval.
Antipsychotics should be avoided during pregnancy especially in the first trimester and should be used only if the benefits outweigh the risks of treatment. Antipsychotics are secreted in breast milk, and it is advised to avoid breastfeeding.
Some antipsychotics can be monitored for a therapeutic range. It is recommended to monitor plasma levels at a trough, which is at a minimum of 12 hours after the last dose, and best at 20 to 24 hours after the last dose. Most antipsychotics do not have a well-defined, dose-response curve.
Haloperidol has a therapeutic range of 2 to 15 ng/ml, chlorpromazine has a range of 30 to 100 ng/ml, and perphenazine has a range of 0.8 to 2.4 ng/ml.
Clozapine shows a better treatment response at a plasma concentration of 350 micrograms per milliliter or higher.
Antipsychotics are widely used medications for a variety of mental health disorders. While effective, these drugs do have many potent side effects. Healthcare workers including pharmacists and nurses need to be aware of the adverse effects because they can seriously affect the quality of life. To avoid the metabolic effects of these drugs, the patient needs to be educated on lifestyle changes. Regular exercise, discontinuation of smoking and eating a healthy diet are important. In addition, at each clinic visit, the patient's body weight, blood cholesterol, blood sugar and blood pressure should be recorded. If the patient is on clozapine, then regular monitoring of the white cell count is highly recommended. Only through strict monitoring can the high morbidity of these drugs be limited. 
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