Typical Antipsychotics

Low potency

Medium potency

High potency

Thioridazine (Mellaril)

Thioridazine (50 to 100 mg p.o. t.i.d.) is indicated in psychosis. Thioridazine has potent anticholinergic properties and causes heavy sedation. However, it produces a very low incidence of extrapyramidal reactions such as akathisia, dystonia, parkinsonism, tardive dyskinesia, and neuroleptic malignant syndrome. Thioridazine is metabolized to mesoridazine, which is an active antipsychotic.

Because of its potent anticholinergic properties, thioridazine should be used cautiously in patients with cardiac diseases such as congestive heart failure, arrhythmias, angina pectoris, or heart block; in encephalitis, Reye’s syndrome, head injury, respiratory disease, epilepsy and other seizure disorders, glaucoma, prostatic hypertrophy, urinary retention, Parkinson’s disease, and pheochromocytoma because the drug may exacerbate these conditions; and in hypocalcemia because it increases the risk of extrapyramidal reactions.

Concomitant use of thioridazine with sympathomimetics, including epinephrine, phenylephrine, phenylpropranolamine, and ephedrine (often found in nasal sprays), and with appetite suppressants may decrease their stimulatory and pressor effects. Thioridazine, having alpha-adrenergic-receptor-blocking effects, may cause epinephrine reversal, where the administration of epinephrine would cause only hypotension.

Thioridazine may inhibit blood pressure response to centrally acting antihypertensive drugs, such as guanethidine, guanabenz, guanadrel, clonidine, methyldopa, and reserpine. Additive effects are likely after concomitant use of thioridazine with CNS depressants, including alcohol, analgesics, barbiturates, narcotics, tranquilizers, anesthetics (general, spinal, or epidural), and parenteral magnesium sulfate (oversedation, respiratory depression, and hypotension), antiarrhythmic agents, including quinidine, disopyramide, and procainamide (increased incidence of cardiac arrhythmias and conduction defects); atropine and other anticholinergic drugs, including antidepressants, MAO inhibitors, antihistamines, meperidine, and antipar-kinsonian agents (oversedation, paralytic ileus, visual changes, and severe constipation); nitrates (hypotension) and metrizamide (increased risk of seizures).

Beta-blocking agents may inhibit thioridazine metabolism, increasing plasma levels and toxicity.

Concomitant use with propylthiouracil increases risk of agranulocytosis; concomitant use with lithium may result in severe neurologic toxicity with an encephalitis-like syndrome and in decreased therapeutic response to thioridazine.

Thioridazine may antagonize the therapeutic effect of bromocriptine on prolactin secretion; it also may decrease the vasoconstricting effects of high-dose dopamine and may decrease effectiveness and increase toxicity of levodopa (by dopamine blockade). Thioridazine may inhibit metabolism and increase toxicity of phenytoin.

Overdose of thioridazine causes CNS depression characterized by deep, unarousable sleep and possible coma, hypotension or hypertension, extrapyramidal symptoms, abnormal involuntary muscle movements, agitation, seizures; arrhythmias, ECG changes, hypothermia or hyperthermia, and autonomic nervous system dysfunction.

Mesoridazine Besylate (Serentil)

Mesoridazine has been used effectively in schizophrenia, behavioral problems in mental deficiency and chronic brain syndrome, alcoholism, and psychoneurotic manifestations associated with neurotic components of personality disorders.

Mesoridazine, a metabolite of thioridazine, is thought to exert its antipsychotic effects by postsynaptic blockade of CNS dopamine receptors, thereby inhibiting dopamine-mediated effects. Mesoridazine has many other central and peripheral affects; it produces both alpha and ganglionic blockade and counteracts histamine- and serotonin-mediated activities. Mesoridazine and thioridazine cause fewer movement disorders (see Phenotheazine Derivatives). Mesoridazine is metabolized to inactive metabolites, which are excreted by the kidneys. Overdosage of mesoridazine causes CNS depression characterized by deep, unarousable sleep, convulsive seizures, and cardiac arrhythmias (see Table Antipsychotic Agents).

Loxapine Hydrochloride (Loxitane C, Loxitane I.M.)

Loxapine Succinate (Loxitane)

Loxapine, a dibenzoxazepine compound, represents a new subclass of tricyclic antipsychotic agents, chemically distinct from the thioxanthenes, butyrophenones, and phe-nothiazines. Chemically, it is a 2-chloro-11-(4-methyl-l-piperazinyl)-dibenz[b,f](1,4)-oxazepine. It is present in capsules as the succinate salt, and in the concentrate and parenteral forms primarily as the hydrochloride salt.

Loxapine (10 mg b.i.d.) is indicated for the treatment of psychotic disorders. It exerts its antipsychotic effects in part by blocking postsynaptic dopamine receptors. It causes moderate sedation, possesses anticholinergic properties, and produces extensive movement disorders such as akathisia, dystonia, parkinsonism, tardive dyskinesia, and neuroleptic malignant syndrome.

Loxapine is absorbed rapidly and completely from the GI tract. Sedation occurs in 30 minutes. Loxapine is distributed widely into the body, including breast milk. Peak effect occurs at 11 / 2 to 3 hours; steady-state serum level is achieved within 3 to 4 days. The drug is 91 to 99% protein bound.

The drug is metabolized extensively by the liver, forming a few active metabolites; duration of action is 12 hours. Most of the drug is excreted as metabolites in urine, some is excreted in feces via the biliary tract. About 50% of the drug is excreted in urine and feces within 24 hours. Similar to phenothiazine derivatives such as chlorpromazine, loxapine should be used cautiously in patients with cardiac disease (arrhythmias, congestive heart failure, angina pectoris, valvular disease, or heart block), encephalitis, Reye’s syndrome, head injury, respiratory disease, epilepsy and other seizure disorders, glaucoma, prostatic hypertrophy, urinary retention, hepatic or renal dysfunction, Parkinson’s disease, or pheochromocytoma. Overdosage with loxapine causes CNS depression characterized by deep, unarousable sleep and possible coma, hypotension or hypertension, extrapyramidal symptoms, abnormal involuntary muscle movements, agitation, seizures, arrhythmias, ECG changes, hypothermia or hyperthermia, and autonomic nervous system dysfunction.

Molindone Hydrochloride (Moban)

Molindone (50 to 75 mg / day) is indicated in the management of the manifestations of psychotic disorders. Molindone is structurally unrelated to the phenothiazines, butyrophenones, or thioxanthenes, but it resembles the piperazine phenothiazines in its clinical action. It causes sedation, possesses anticholinergic properties and, similar to fluphenazine, produces movement disorders. Molindone is metabolized, and the metabolites are excreted in the urine. It lowers the seizure threshold and may cause seizures in patients with epilepsy and other seizure disorders. Concomitant use with sympathomimetics, including epinephrine, phenylephrine, phenylpropanolamine, and ephedrine (often found in nasal sprays), or appetite suppressants may decrease their stimulatory and pressor effects. Because of its alpha-blocking potential, molindone may cause epinephrine reversal — a hypotensive response to epinephrine.

Molindone may inhibit blood pressure response to centrally acting antihypertensive drugs, such as guanethidine, guanabenz, guanadrel, clonidine, methyldopa, and reserpine. Additive effects are likely after concomitant use of molindone with CNS depressants, including alcohol, analgesics, barbiturates, narcotics, tranquilizers, and general, spinal, or epidural anesthetics, or parenteral magnesium sulfate (oversedation, respiratory depression, and hypotension); antiarrhythmic agents, quinidine, disopyramide, or procainamide (increased incidence of cardiac arrhythmias and conduction defects); atropine or other anticholinergic drugs, including antidepressants, monoamine oxidase inhibitors, phenothiazines, antihistamines, meperidine, and antiparkinsonian agents (oversedation, paralytic ileus, visual changes, and severe constipation); nitrates (hypotension); and metrizamide (increased risk of convulsions). Beta-blocking agents may inhibit molindone metabolism, increasing plasma levels and toxicity. Concomitant use with propylthiouracil increases risk of agranulocytosis; concomitant use with lithium may result in severe neurologic toxicity, with an encephalitis-like syndrome and a decreased therapeutic response to molindone. Decreased therapeutic response to molindone may follow concomitant use with calcium-containing drugs such as phenytoin and tetracyclines, aluminum- and magnesium-containing antacids or antidiarrheals (decreased absorption), or caffeine (increased metabolism). Molindone may antagonize the therapeutic effect of bromocriptine on prolactin secretion; it may also decrease the vasoconstricting effects of high-dose dopamine and may decrease effectiveness and increase toxicity of levodopa (by dopamine blockade). Calcium sulfate in molindone tablets may inhibit the absorption of phenytoin or tetracyclines (see Table Antipsychotic Agents).

Perphenazine (Trilafon)

Perphenazine, a phenothiazine (4 to 8 mg t.i.d.), is indicated in the management of psychotic disorders, in the control of nausea and vomiting in adults, and in the relief of intractable hiccups.

Perphenazine is thought to exert its antipsychotic effects by postsynaptic blockade of CNS dopamine receptors, thus inhibiting dopamine-mediated effects. The antiemetic effects of perphenazine are attributed to dopamine-receptor blockade in the medullary chemoreceptor trigger zone. Perphenazine has many other central and peripheral effects; it produces both alpha and ganglionic blockade and counteracts histamine- and serotonin-mediated functions. It produces a very high incidence of movement disorders including akathisia, dystonia, parkinsonism, tardive dyskinesia, and neuroleptic malignant syndrome. Perphenazine possesses anticholinergic properties and hence should be used cautiously in patients with arrhythmias, CHF, angina pectoris, valvular disease, heart block, encephalitis, Reye’s syndrome, head injury, respiratory disease, epilepsy and other seizure disorders (the drug may lower the seizure threshold), glaucoma (the drug may raise intraocular pressure [IOP]), prostatic hypertrophy, Parkinson’s disease, urinary retention (the drug may worsen these conditions), and hepatic or renal dysfunction (impaired metabolism and excretion may cause drug accumulation).

Concomitant use of perphenazine with sympathomimetics, including epinephrine, phenylephrine, phenylpropanolamine, and ephedrine (often found in nasal sprays), and with appetite suppressants may decrease their stimulatory and pressor effects. Phenothiazines can cause epinephrine reversal and a hypotensive response when epinephrine is used for its pressor effects.

Perphenazine may inhibit BP response to centrally acting antihypertensive drugs such as guanethidine, guanabenz, guanadrel, clonidine, methyldopa, and reserpine. Additive effects are likely after concomitant use of perphenazine with CNS depressants, including alcohol, analgesics, barbiturates, narcotics, tranquilizers, and general, spinal, or epidural anesthetics, or parenteral magnesium sulfate (oversedation, respiratory depression, and hypotension); antiarrhythmic agents, quinidine, disopyramide, and procainamide (increased incidence of cardiac dysrhythmias and conduction defects); atropine or other anticholinergic drugs, including antidepressants, monoamine oxidase inhibitors, phenothiazines, antihistamines, meperidine, and antiparkinsonian agents (oversedation, paralytic ileus, visual changes, and severe constipation); nitrates (hypotension) and metrizamide (increased risk of convulsions). Beta-blocking agents may inhibit perphenazine metabolism, increasing plasma levels and toxicity.

Thiothixene Hydrochloride (Intensol)

Thiothixene (2 mg t.i.d. in mild cases) is indicated in the management of psychotic disorders. Thiothixene and chlorprothixene are thioxanthene antipsychotics. Their select pharmacological properties are compared with chlorpromazine and haloperidol and are shown in Table.

Trifluoperazine Hydrochloride (Stelazine)

Trifluoperazine, a phenothiazine antipsychotic with anti-emetic properties (2 to 5 mg p.o. t.i.d.), is indicated in the management of manifestations of psychotic disorders (see Table Antipsychotic Agents).

Trifluoperazine exerts its antipsychotic effects by postsynaptic blockade of CNS dopamine receptors, thereby inhibiting the action of dopamine.

Trifluoperazine’s antiemetic effects are attributed to dopamine-receptor blockade in the medullary chemoreceptor trigger zone.

Trifluoperazine exhibits low incidences of sedative and anticholinergic properties, but causes a high incidence of extrapyramidal movement disorders including akathisia, dystonia, parkinsonism, tardive dyskinesia, and neuroleptic malignant syndrome.

Concomitant use of trifluoperazine with sympathomimetics, including epinephrine, phenylephrine, phenylpropanolamine, and ephedrine (often found in nasal sprays), and appetite suppressants may decrease their stimulatory and pressor effects. Using epinephrine as a pressor agent in patients taking trifluoperazine may result in epinephrine reversal or further lowering of blood pressure.

Trifluoperazine may inhibit blood pressure response to centrally acting antihypertensive drugs, such as guanethidine, guanabenz, guanadrel, clonidine, methyldopa, and reserpine. Additive effects are likely after concomitant use of trifluoperazine with CNS depressants, including alcohol, analgesics, barbiturates, narcotics, tranquilizers, anesthetics (general, spinal, epidural), and parenteral magnesium sulfate (oversedation, respiratory depression, and hypotension); antiarrhythmic agents, quinidine, disopyramide, and procainamide (increased incidence of cardiac arrhythmias and conduction defects); atropine and other anticholinergic drugs, including antidepressants, monoamine oxidase inhibitors, phenothiazines, antihistamines, meperidine, and antiparkinsonian agents (oversedation, paralytic ileus, visual changes, and severe constipation); nitrates (hypotension); and metrizamide (increased risk of seizures).

The clinical manifestations of overdosage of trifluoperazine include CNS depression characterized by deep, unarousable sleep and possible coma, hypotension or hypertension, extrapyramidal symptoms, dystonia, abnormal involuntary muscle movements, agitation, seizures, arrhythmias, ECG changes, hypothermia or hyperthermia, and autonomic nervous system dysfunction.

Haloperidol (Haldol Tablets 0.5mg)

Haloperidol is a phenylbutylpiperadine derivative antipsychotic, apparently caused by dopamine-receptor blockage in CNS. It is indicated in the management of psychotic disorders; control of Tourette’s disorder in children and adults; management of severe behavioral problems in children; short-term treatment of hyperactive children; and long-term antipsychotic therapy (haloperidol decanoate).

Haloperidol is a butyrophenone derivative with antipsychotic action similar to that of piperazine phenothiazines such as fluphenazine. Haloperidol (0.5 to 2 mg t.i.d.) is indicated in the management of psychotic disorders; in Tourette’s disorder for the control of tics and vocal utterances; in severe behavioral problems of children with combative and explosive nature; in hyperactive impulse disorder in children associated with aggression, low frustration tolerance, and impulsive behavior, and in elderly subjects with senile dementia.

Haloperidol blocks dopamine receptors in the brain and hence produces a very high incidence of movement disorders such as parkinsonism (see phenothiazine derivatives). Its mechanism of action in Gilles de la Tourette’s syndrome is unknown. In addition to blocking dopamine receptors, haloperidol has many other central and peripheral effects; it has weak peripheral anticholinergic and antiemetic effects, produces both alpha and ganglionic blockade, and counteracts histamine- and serotonin-mediated activities.

Haloperidol is absorbed well orally and intramuscularly (haloperidol decanoate), distributed widely in the body while accumulating in adipose tissue, binds to protein heavily (90 to 99%), and is metabolized in the liver. Haloperidol is eliminated unchanged in the feces and urine to the extent of 15 and 40%, respectively.

The highest incidence of adverse effects of haloperidol include the CNS-involving extrapyramidal symptoms such as dystonia, akathisia, parkinsonism, tardive dyskinesia, and neuroleptic malignant syndrome. Overdose with haloperidol causes CNS depression characterized by deep, unarousable sleep and possible coma, hypotension or hypertension, extrapyramidal symptoms, dystonia, abnormal involuntary movements, agitation, seizures, arrhythmias, ECG changes (may show QT prolongation and torsade de pointes), hypothermia or hyperthermia, and autonomic nervous system dysfunction. Overdose with long-acting decanoate requires prolonged recovery time. Treatment is symptomatic and supportive in nature (see Table Antipsychotic Agents).

Fluphenazine Hydrochloride (Prolixin)

Fluphenazine (0.5 to 10 mg p.o. daily in divided doses q. 6 to 8 hours) is indicated in the management of manifestations of psychotic disorders. As depicted in Table 2, its potency equals that of haloperidol. In addition, similar to haloperidol it produces movement disorders such as akathisia, dystonia, parkinsonism, neuroleptic malignant syndrome, and tardive dyskinesia. The drug is available as fluphenazine decanoate and fluphenazine enanthate which are intended for depot injection, with an onset of action of 24 to 72 hours, and a duration of action of two weeks. Neuroleptics are not of any value if patients do not take them at the dosage that has been prescribed, or if their bodies do not absorb the orally administered drug effectively. It has been estimated that 10 to 25% of schizophrenic inpatients somehow fail to ingest the prescribed dosage, and that 25 to 50% of schizophrenic outpatients deviate from or default on their medication regimens. This has obvious consequences in terms of the relapse rate and revolving door syndrome.

The development of long-acting formulations, both injectable and oral, carries the potential to remedy these two treatment liabilities. These new formulations have already made an impact on the treatment of the unreliable drug taker, the poor oral absorbers, and those patients being treated in outpatient settings who are too ill to assume responsibility for their own drug taking. These long-acting psychotropics are remarkably free of side effects when given for extended periods. Full blood counts, urinalysis, and renal function tests are essentially normal, even after years of continuous treatment with these drugs. The only significant hazard that is associated with the continuous, prolonged use of these medications is tardive dyskinesia. There are indications, however, that the injectable psycho-tropic drugs produce less, or less persistent, tardive dyskinesia than do the orally administered neuroleptics. This is probably due to the fact that the injectable forms can be given in lower dosages. See also Phenothiazine Derivatives.

Droperidol (Inapsine)

Droperidol is used as an adjunct for induction and maintenance of general anesthesia and as an anesthetic in diagnostic procedures. Droperidol, which has antiemetic properties, causes marked sedation and potentiates the CNS depressant effects of alcohol, hypnotic-sedatives, and numerous psychoactive agents. Droperidol is absorbed well through an IM injection — sedation begins in 3 minutes, peaks at 30 minutes, and lasts for 2 to 4 hours. Droperidol is metabolized by the liver to p-fluoro-phenylacetic acid and p-hydroxypiperidine, and its metabolites are excreted in urine and feces.

Prochlorperazine (Compazine)

Prochlorperazine, an antiemetic and antipsychotic agent, is indicated in controlling preoperative nausea (5 to 10 mg IM 1 to 2 hours before induction of anesthesia) and severe nausea and vomiting (5 to 10 mg p.o. t.i.d.) associated with circulating physical agents (radiation therapy and virus particles) and chemical agents (toxins and cancer chemotherapeutic agents).

Prochlorperazine is thought to exert its antipsychotic effects by postsynaptic blockade of CNS dopamine receptors, thus inhibiting dopamine-mediated effects. Its anti-emetic effects are attributed to dopamine receptor blockade in the medullary chemoreceptor trigger zone.

Prochlorperazine causes sedation, has weak anticholin-ergic properties, and produces a high incidence of movement disorders.

Concomitant use of prochlorperazine with sympathomimetics, including epinephrine, phenylephrine, phenylpropranolamine, and ephedrine (often found in nasal sprays), and with appetite suppressants may decrease their stimulatory and pressor effects and may cause epinephrine reversal (hypotensive response to epinephrine).

Prochlorperazine may inhibit BP response to centrally acting antihypertensive drugs such as guanethidine, guanabenz, guanadrel, clonidine, methyldopa, and reserpine. Additive effects are likely after concomitant use of prochlorperazine with CNS depressants, including alcohol, analgesics, barbiturates, narcotics, tranquilizers, and anesthetics (general, spinal, or epidural), and parenteral magnesium sulfate (oversedation, respiratory depression, and hypotension); antiarrhythmic agents, quinidine, disopyramide, and procainamide (increased incidence of cardiac arrhythmias and conduction defects); atropine and other anticholinergic drugs, including antidepressants, monoamine oxidase inhibitors, phenothiazines, antihistamines, meperidine, and antiparkinsonian agents (oversedation, paralytic ileus, visual changes, and severe constipation); nitrates (hypotension); and metrizamide (increased risk of convulsions).

Beta-blocking agents may inhibit prochlorperazine metabolism, increasing plasma levels and toxicity.

Concomitant use with propylthiouracil increases the risk of agranulocytosis; concomitant use with lithium may result in severe neurologic toxicity with an encephalitis-like syndrome, and in decreased therapeutic response to prochlorperazine.

Pharmacokinetic alterations and subsequent decreased therapeutic response to prochlorperazine may follow concomitant use with phenobarbital (enhanced renal excretion); aluminum- and magnesium-containing antacids and antidiarrheals (decreased absorption); caffeine, or heavy smoking (increased metabolism).

Prochlorperazine may antagonize the therapeutic effect of bromocriptine on prolactin secretion; it also may decrease the vasoconstricting effects of high-dose dopamine and may decrease effectiveness and increase toxicity of levodopa (by dopamine blockade). Prochlorperazine may inhibit metabolism and increase toxicity of phenytoin.

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