Typical antipsychotics

Typical antipsychotics

 INTRODUCTION

    Antipsychotic medication is the  general term that refers to a diverse group of pharmacologic agents  that are effective in the symptomatic treatment of   psychoses. These medication have also been reffered to as major  traqulisers or neuroleptics.  These  drugs fall into 2 major  groups  , Typical/ Traditional antipsychotics & Atypical antipsychotics.¹

TYPICAL ANTIPSYCHOTIC  AGENTS

Classification

The traditional antipsychotics can be classified by potency or by chemical structure. From a clinical viewpoint, clas­sification by potency is more informative.²

Classification by Potency    

Traditional antipsychotic agents can be classified as low potency, medium potency, or high potency The low-potency drugs, represented by chlorpromazine, and the high-potency drugs, represented by haloperidol, are of particular interest.²

It is important to note that, although the traditional an­tipsychotics differ from one another in potency, all of these drugs are essentially equal in their ability to relieve symptoms of psychoses. Recall that the term potency refers only to the size of the dose needed to elicit a given response; potency implies nothing about the maximal effect that a drug can produce. Hence, when we say that haloperidol is more potent than chlorpromazine, we mean only that the dose of haloperidol required to relieve psychotic symptoms is smaller than the required dose of chlorpromazine; we do not mean that haloperidol can produce greater effects. When administered in therapeutically equivalent doses, both drugs elicit an equivalent antipsychotic response.

Chemical Classification

The traditional antipsychotic agents can be placed into five major groups based on their chemical structures. ²

One of these groups, the phenothiazines, has three subdivisions. Drugs in all groups are equivalent with respect to antipsychotic actions. Because of this equivalence, chemical classification is not emphasized in this chapter.

Two chemical categories—the phenothiazines and the butyrophenones—deserve special attention.

The phenothiazines were the first of the modern antipsychotic agents. Chlorpromazine, our prototype of the low-potency neuroleptics, is a member of the phenothiazine family. The butyrophenones stand out because they are the family to which haloperidol belongs. Haloperidol is the prototype of the high-potency antipsychotics

ANTIPSYCHOTIC DRUGS; ROUTES AND DOSAGE

Chemical  class& generic name	Trade name	route	Total daily dose  short term(mg)	Total daily dose   maintenance (mg)
Phenothiazine;  aliphatic
Chlorpromazine	Largactil,Thorazine	PO,IM	200 -  1000	50-  400
Tiflupromazine	Vesprin	IM	30 -  150	20  - 100
Phenothiazine ; piperidine
Mesoridazine	Serentil	PO  ,IM	100  -400	25  -200
Thioridazine	Mellaril	PO	200   -  800	50  -  400
Phenothiazine;  piperazine
Acetophenazine	Tindal	PO	60  -  150	40   -  80
Fluphenazine	Prolixin	PO , IM	5 -50	1-      15
Perphenazine	Trilafon	PO, IM	12  -64	8  -24
Trifluoperazine	Telecalm	PO	10  -60	4  -  30
Thioxanthene
Thiothixene	Navane	PO, IM	10-  60	6  -30
Butyrophenone
Haloperidol	Haldol	PO , IM	5  -50	1  -15
Dihyrdoindolone
Molindone	Moban	PO	40  - 225	15  -  100
Dibenzoxazepine
Loxapine	Loxitane	PO  ,IM	20  - 160	10 - 60

Mechanism of Action

The traditional antipsychotic drugs block a variety of receptors within and outside the CNS. To varying degrees, these drugs block receptors for dopamine, acetylcholine (muscarinic), histamine, and norepinephrine (alpha1). Blockade at these receptors is responsible for the major adverse effects of the antipsychotics. However, since the etiology of psychotic illness is entirely unknown, the relationship of receptor blockade to therapeutic effects can only be guessed. The current dominant theory suggests that traditional anti­psychotic drugs suppress symptoms of psychosis by blocking dopamine2 (D2) receptors in the mesolimbic and mesocortical areas of the brain, regions thought to be involved in the expression of psychotic symptoms. In support of this theory is the observation that all of the traditional antipsychotics produce D2 receptor blockade. Furthermore, there is a close correlation between the clinical potency of these drugs and their potency as D2 receptor antagonists.

Factors Influencing the Pharmacokinetics of Antipsychotics1

Age Elderly patients may demonstrate reduced clearance rates. Medical condition Decreased hepatic blood flow can reduce clearance. Hepatic disease can decrease clearance. Enzyme inducers Carbamazepine, phenytoin, ethambutol, barbiturates Clearance inhibitors Include selective serotonin reuptake inhibitors, tricyclic antidepressants, cimetidine, β-blockers, isoniazid, methylphenidate, erythromycin, triazolobenzodiazepines, ciprofloxacin, ketoconazole. Changes in binding protein Hypoalbuminemia can occur with malnutrition or hepatic failure.

THERAPEUTIC USES

1.      Schizophrenia.

 Schizophrenia is the primary indication for antipsychotic drugs. These agents effectively suppress symptoms during acute psychotic episodes, and, when taken chronically, can greatly decrease the risk of relapse. Initial effects may be seen in 1 to 2 days, but substantial improvement usually takes 2 to 4 weeks, and full effects may not develop for several months. Positive symptoms (e.g., delusions, hallucinations) respond better than nega­tive symptoms (e.g., social and emotional withdrawal, blunted affect, poverty of speech). ²

2.      Bipolar Disorder (Manic-Depressive Illness).

Most patients with bipolar disorder are managed with lithium, the drug of choice for this disease. Neuroleptics may be employed acutely (in combination with lithium) to help manage patients going through a severe manic phase.

3.      Tourette’s Syndrome.

 This rare inherited disorder is characterized by severe motor tics, barking cries, grunts, and outbursts of obscene language, all of which are spontaneous and beyond the control of the patient. At least three antipsychotic drugs— pimozide, fluphenazine, and haloperidol—can help suppress severe symptoms. For mild symptoms, clonidine is the drug of choice.

4.      Prevention of Emesis.

Neuroleptics suppress emesis by blocking dopamine receptors in the chemoreceptor trigger zone of the medulla. These drugs can be employed to suppress vomiting associated with cancer chemotherapy, gastroenteritis, uremia, and other conditions.

5.      Other Applications.

 Neuroleptics can be used for dementia and other organic mental syndromes (psychiatric syndromes resulting from organic causes, such as infection, metabolic disorders, poisoning, and structural injury to the brain), delusional disorders, and schizoaffective disorder. In addition, these agents can relieve symptoms of Huntington’s chorea.

ADVERSE EFFECTS

Although antipsychotic agents produce a variety of undesired effects, these drugs are, on the whole, very safe; death from over dosage is practically unheard of. Of the many side effects these drugs can produce, the most troubling are the extrapyramidal reactions, especially tardive dyskinesia.

a)     Extrapyramidal Side Effects

Extrapyramidal side effects (EPSE) are movement disorders resulting from effects of antipsychotic drugs on the extrapyramidal motor system. The extrapyramidal system is the same neuronal network whose malfunction is responsible for the movement disorders of Parkinson’s disease. Although the exact cause of EPSE is unclear, blockade of D2 receptors is strongly suspected.

Four types of EPSE occur. These differ from one another with respect to time of onset and management. Three of these reactions—acute dystonia, Parkinsonism, and akathisia—occur early in therapy and can be managed with a variety of drugs. The fourth reaction—tardive dyskinesia—occurs late in therapy and has no satisfactory treatment.

The early reactions occur less frequently with low-potency agents (e.g., chlorpromazine) than with high-potency agents (e.g., haloperidol). In contrast, the risk of tardive dyskinesia is equal with all antipsychotics.

B) Acute Dystonia.

Acute dystonia can be both disturbing and dangerous. The reaction develops within the first few days of therapy, and frequently within hours of the first dose. Typically, the patient develops severe spasm of the muscles of the tongue, face, neck, or back. Oculogyric crisis (involuntary upward deviation of the eyes) and opisthotonus (tetanic spasm of the back muscles causing the trunk to arch forward, while the head and lower limbs are thrust backward) may also occur. Severe cramping can cause joint dislocation. Laryngeal dystonia can impair respiration.

Intense dystonia constitutes a crisis that requires rapid intervention. Initial treatment consists of anticholinergic medication (e.g. benztropine, diphenhydramine) administered IM or IV. As a rule, symptoms resolve within 5 rninutes of IV administration and within 15 to 20 minutes of IM administration.

It is important to differentiate between acute dystonia and psychotic hysteria. Misdiagnosis of acute dystonia as hysteria could result in escalation of antipsychotic dosage, -thereby causing the acute dystonia to become even worse.¹

C) Parkinsonism. Antipsychotic-induced parkinsonism is characterized by bradykinesia, mask-like facies, drooling, tremor, rigidity, shuffling gait, cogwheeling, and stooped posture. Symptoms develop within the first month of therapy and are indistinguishable from those of idiopathic Parkinson’s disease.

Neuroleptics cause parkinsonism by blocking dopa­mine receptors in the striatum. Since idiopathic Parkinson’s disease is also due to reduced activation of striatal dopamine receptors , it is no wonder that Parkinson’s disease and neuroleptic-induced parkinsonism share the same symptoms.

Neuroleptic-induced parkinsonism is treated with some—but not all—of the drugs used to treat Parkinson’s disease. Specifically, centrally acting anticholinergic drugs (e.g., benztropine, diphenhydramine) and amantadine [Symmetrel] may be employed. Levodopa, however, should be avoided, since this drug promotes activation of dopamine receptors, and might thereby counteract the beneficial effects of antipsychotic treatment.

D) Akathisia.

 Akathisia is characterized by pacing and squirming brought on by an uncontrollable need to be in motion. This profound sense of restlessness can be very disturbing. The syndrome usually develops within the first 2 months of treatment. Like other early extrapyramidal reactions, akathisia occurs most frequently with high-potency antipsychotics.

Three types of drugs have been used to suppress symptoms: beta blockers, benzodiazepines, and anticholinergic drugs. Although these can be helpful, a reduction in antipsychotic dosage or switching to a low-potency agent may be more effective.

It is important to differentiate between akathisia and exacerbation of psychosis. If akathisia were to be confused with anxiety or psychotic agitation, it is likely that antipsychotic dosage would be increased, thereby making akathisia more intense.

E) Tardive Dyskinesia.

Tardive dyskinesia (TD), the most troubling EPSE, develops in 15% to 20% of patients during long-term therapy. The risk is related to duration of treatment and dosage size. For many patients, symptoms are irreversible.

TD is characterized by involuntary choreoathetoid (twisting, writhing, worm-like) movements of the tongue and face. Patients may also present with lip-smacking movements, and their tongues may flick out in a “fly-catching” motion. One of the earliest manifestations of TD is slow, worm-like movement of the tongue. Involuntary movements that involve the tongue and mouth can interfere with chewing, swallowing, and speaking. Eating difficulties can result in malnutrition and weight loss. Over time, TD produces involuntary movements of the limbs, toes, fingers, and trunk. For some patients, symptoms decline following a dosage reduction or drug withdrawal. For others, TD is irreversible.

The cause of TD is complex and incompletely understood. One theory suggests that symptoms result from excessive activation of dopamine receptors. It is postulated that, in response to chronic receptor blockade, dopamine receptors of the extrapyramidal system undergo a functional change such that their sensitivity to activation is increased. Stimulation of these “supersensitive” receptors produces an imbalance in favor of dopamine, and thereby produces abnormal movement. In support of this theory is the observation that symptoms of TD can be reduced (temporarily) by increasing antipsychotic dosage, which causes greater dopamine receptor blockade. (Since symptoms eventually return even though antipsychotic dosage is kept at an elevated level, dosage elevation cannot be used to treat TD.)

There is no reliable management for TD. Measures that may be tried include gradual withdrawal of anticholinergic drugs, administration of benzodiazepines, and reducing the dosage of the offending antipsychotic agent. For patients with severe TD, switching to clozapine or risperidone (atypical antipsychotic agents) may be beneficial. These drugs do not seem to cause TD, and may actually suppress symptoms in patients who have developed the disorder.

Since TD has no reliable means of treatment, prevention is the best approach. Antipsychotic drugs should be used in the lowest effective dosage for the shortest time required. After 12 months, the need for continued therapy should be assessed. If drug use must continue, a neurologic evaluation should be done at least every 3 months to detect early signs of TD. For patients with chronic schizophrenia, dosage should be tapered periodically (at least annually) to determine the need for continued treatment.³

Other Adverse Effects

1.      Neuroleptic Malignant Syndrome.

 Neuroleptic malignant syndrome (NMS) is a rare but serious reaction that carries a 4% risk of mortality (down from 30% a decade ago thanks to early diagnosis and intervention). Primary symptoms are “lead-pipe” rigidity, sudden high fever (teperature may exceed 4l°C), sweating, and autonomic in­stability, manifested as dysrhythmias and fluctuations in blood pressure. Level of consciousness may rise and fall, the patient may appear confused or mute, and seizures or coma may develop. Death can result from respiratory failure, cardiovascular collapse, dysrhythmias, and other causes. NMS is more likely with high-potency agents than with low-potency agents.

Treatment consists of supportive measures, drug therapy, and immediate withdrawal of antipsychotic medication. Hyperthermia should be controlled with cooling blankets and antipyretics (e.g., aspirin, acetaminophen). Hydration should be maintained with fluids. Benzodiazepines may relieve anxiety and help reduce blood pressure and tachycardia. Two drugs—dantrolene and bromocriptine—may be especially helpful. Dantrolene is a direct-acting muscle relaxant. In patients with NMS, this drug reduces rigidity and hyperthermia. Bromocriptine is a dopamine receptor agonist that may relieve CNS toxicity.

2.      Anticholinergic Effects.

 Antipsychotic drugs produce varying degrees of muscarinic cholinergic blockade. By blocking muscarinic receptors, these drugs can elicit a full spectrum of anticholinergic responses (dry mouth, blurred vision, photophobia, urinary hesitancy, constipation, and tachycardia). Patients should be informed about these responses and taught how to minimize danger and discomfort.

3.      Orthostatic Hypotension.

Antipsychotic drugs promote orthostatic hypotension by blocking alpharadrenergic receptors on blood vessels. Alpha-adrenergic blockade prevents compensatory vasoconstriction when the patient stands; hence, blood pressure falls. Patients should be informed about signs of hypotension (lightheadedness, dizziness) and advised to sit or lie down if these occur. In addition, patients should be informed that hypotension can be minimized by moving slowly when assuming an erect posture. With hospitalized patients, blood pressure and pulses should be checked before drug administration and 1 hour after. Measurements should be made while the patient is lying down and again after the patient has been sitting or standing for 1 to 2 minutes. If blood pressure is low, or if pulse rate is high, the drug should be withheld and the physician consulted. Hypotension is more likely with low-potency antipsychotics than with the high-potency drugs. Tolerance to hypotension develops in 2 to 3 months.¹

4.      Sedation.

Sedation is common during the early days of treatment but subsides within a week or so. Neuroleptic-induced sedation is thought to result from blockade of histamine receptors in the CNS. Daytime sedation can be minimized by administering the entire daily dose at bed­time. Patients should be warned against participation in hazardous activities (e.g., driving) until sedative effects diminish.

5.      Neuroendocrine  Effects.

Antipsychotics increase levels of circulating prolactin by blocking the inhibitory action of dopamine on prolactin release. Elevation of prolactin levels promotes gynecomastia (breast growth) and galactorrhea in up to 57% of women. Up to 97% experience menstrual irregularities. Gynecomastia and galactorrhea can also occur in males. Since prolactin can promote growth of prolactin-dependent carcinoma of the breast, neuroleptics should be avoided in patients with this form of cancer. (It should be noted that, although antipsychotic drugs can promote the growth of cancers that already exist, there is no evidence that antipsychotic drugs actually cause cancer.)

6.      Seizures.

Antipsychotic drugs can reduce seizure threshold, thereby increasing the risk of seizure activity. The risk of seizures is greatest in patients with epilepsy and other seizure disorders. These patients should be monitored, and, if loss of seizure control occurs, the dosage of their antiseizure medication must be increased.

7.      Sexual Dysfunction.

 Antipsychotics can cause sexual dysfunction in women and men. In women, these drugs can suppress libido and impair the ability to achieve orgasm. In men, neuroleptics can suppress libido and cause erectile and ejaculatory dysfunction; the incidence of these effects is 25% to 60%. Drug-induced sexual dysfunction can make treatment unacceptable to sexually active patients, thereby leading to poor compliance..

8.      Dermatologic Effects.

 Drugs in the phenothiazine class can sensitize the skin to ultraviolet light, thereby increasing the risk of severe sunburn. Patients should be warned against excessive exposure to sunlight and advised to apply a sunscreen and wear protective clothing. Phenothiazines can also produce pigmentary deposits in the skin, cornea, and lens of the eye.

Handling antipsychotics can cause contact dermatitis in patients and health care personnel. Dermatitis can be prevented by avoiding direct contact with these drugs.

9.      Agranulocytosis.

 Agranulocytosis is a rare but serious reaction. Among the traditional antipsychotics, the risk is highest with chlorpromazine and certain other phenothiazines. Since agranulocytosis severely compromises the ability to fight infection, white blood cell counts should be done whenever signs of infection (e.g., fever, sore throat) appear. If agranulocytosis is diagnosed, the neuroleptic should be withdrawn. Agranulocytosis reverses upon discontinuation of treatment.

DRUG INTERACTIONS

Anticholinergic Drugs: - Drugs with anticholinergic properties will intensify anticholinergic responses to neuroleptics. Patients should be advised to avoid all drugs with anticholinergic actions, including antihistamines and certain over-the-counter sleep aids.

CNS Depressants. Neuroleptics can intensify CNS depression caused by other drugs. Patients should be warned against using alcohol and all other drugs with CNS-depressant actions (e.g., antihistamines, benzodiazepines, barbiturates).

Levodopa.

Levodopa may counteract the antipsychotic effects of neuroleptics. Conversely, neuroleptics may counteract the therapeutic effects of levodopa. These interactions occur because levodopa and neuroleptics have opposing effects on receptors for dopamine: levodopa activates these receptors, whereas neuroleptics cause blockade.

LOW-POTENCY AGENTS

Chlorpromazine

Chlorpromazine [Thorazine] was the first modern antipsychotic medication and is the prototype for all that followed. None of the newer agents is superior at relieving symptoms of psychotic illnesses. Chlorpromazine is a low-potency neuroleptic and belongs to the phenothiazine family of compounds.¹

Therapeutic Uses. Principal indications for chlorpromazine are schizophrenia and other psychotic disorders. Additional psychiatric indications are schizoaffective disorder and the manic phase of bipolar disorder. Other uses include suppression of emesis and relief of intractable hiccoughs.

Pharmacokinetics. Chlorpromazine may be administered orally, IM, and by rectal suppository. Following oral administration, the drug is well absorbed but undergoes extensive first-pass metabolism. As a result, oral bioavailability is only 30%. When chlorpromazine is given by IM injection, peak plasma levels are 10 times those achieved with an equal oral dose. Excretion is renal, almost entirely as metabolites.

Adverse Effects. The most common adverse effects are sedation, orthostatic hypotension, and anticholinergic effects (dry mouth, blurred vision, urinary retention, photophobia, constipation, and tachycardia). Neuroendocrine effects— galactorrhea, gynecomastia, and menstrual irregularities— occur occasionally. Photosensitivity reactions are possible, and patients should be warned to minimize unprotected exposure to sunlight. Because chlorpromazine is a low-potency neuroleptic, the risk of early extrapyramidal reactions (dystonia, akathisia, Parkinsonism) is relatively low. However, the risk of tardive dyskinesia is the same as with all other traditional agents. Chlorpromazine lowers seizure threshold; hence patients with seizure disorders should be especially diligent about taking antiseizure medication. Agranulocytosis and neuroleptic malignant syndrome occur rarely.

Drug Interactions. Chlorpromazine can intensify responses to CNS depressants (e.g., antihistamines, benzodiazepines, barbiturates) and anticholinergic drugs (e.g., antihistamines, tricyclic antidepressants, atropine-like drugs).

Preparations, Dosage, and Administration. Chlorpromazine [Thorazine, Ormazine] is available in six formulations: tablets (10, 25, 50, 100, and 200 mg), sustained-release capsules (30, 75, 150, 200, and 300 mg), syrup (2 mg/ml), liquid concentrate (30 and 100 mg/ml), rectal suppositories (25 and 100 mg), and injection (25 mg/ml).

Oral Therapy. The initial dosage for adults is 25 mg 3 times a day. Dosage should be gradually increased until symptoms are controlled. The usual maintenance dosage is 400 mg/day. Elderly patients require fewer drugs than younger patients.

Parenteral Therapy. Parenteral therapy is indicated for the acutely psychotic, hospitalized patient. Intramuscular administration is preferred to intravenous. (Intravenous chlorpromazine is highly irritating and is generally avoided.) The initial dose is 25 to 50 mg. Dosage may be increased gradually to a maximum of 400 mg every 4 to 6 hours. Once symptoms are controlled, oral therapy should be substituted for parenteral.

A prospective, uncontrolled clinical trial was conducted by Kenneth V Iserson to test the safety and efficacy of intramuscular chlorpromazine (1 mg/kg) in the acute, outpatient treatment of migraine. One hundred adult patients were included in the study. There was complete relief of both pain and nausea/emesis symptoms in 96 patients within 55 minutes of the injection. Eighteen patients experienced orthostatic hypotension following injection. All but one responded to noninvasive therapy. The results suggest that chlorpromazine is a safe, effective alternative medication in the outpatient treatment of acute migraine.⁷

Thioridazine

Thioridazine [Mellaril] is a low-potency agent indicated for schizophrenia and other psychotic disorders. The drug belongs to the piperidine subclass of phenothiazines. The most common adverse effects are sedation, orthostatic hypotension, anticholinergic effects, weight gain, and inhibition of ejaculation. Effects seen occasionally include extrapyramidal reactions (dystonia, Parkinsonism, akathisia, tardive dyskinesia), galactorrhea, gynecomastia, menstrual irregularities, and photosensitivity reactions. Neuroleptic malignant syndrome, convulsions, agranulocytosis, and pigmentary retinopathy occur rarely. Principal interactions are with anticholinergic drugs and CNS depressants. Thioridazine is dispensed in tablets (10, 15, 25, and 50 mg) for oral use. The initial dosage is 50 to 100 mg 3 times a day. Dosage may be gradually increased until symptoms are controlled, but should not exceed 800 mg/day. The usual maintenance dosage is 200 to 800 mg/day in two to four divided doses.

MEDIUM-POTENCY AGENT

Loxapine.

 Loxapine is a medium-potency agent indicated for schizophrenia and other psychotic disorders. The drug’s side-effect profile is similar to that of fluphenazine. Administration is oral and intramuscular. Three formulations are available: capsules (5, 10, 25, and 50 mg), liquid concentrate (25 mg/ml), and injection (50 mg/ml). The initial oral dosage is 10 mg twice daily. Dosage is increased until symptoms are controlled, typically with 60 to 100 mg/day in divided doses. The dosage should be reduced for maintenance therapy; the usual range is 20 to 60 mg/day. The intramuscular dosage is 12.5 to 50 mg every 4 to 6 hours.

Perphenazine.

 Perphenazine is a medium-potency agent used to treat schizophrenia and other psychotic disorders. The drug’s side-effect profile is like that of fluphenazine. For therapy of psychotic disorders, perphenazine is given orally and by IM injection. Three formulations are available: tablets (2, 4, 8, and 16 mg), liquid concentrate (16 mg/5 ml), and injection (5 mg/ml). The initial oral dosage is 4 to 8 mg 3 times daily. Once symptoms have been controlled, the dosage should be reduced to the lowest effective amount. The initial intramuscular dosage is 5 mg every 6 hours. Parenteral dosage should not exceed 15 mg/24 hours in ambulatory patients or 30 mg/24 hours in hospitalized patients.

HIGH-POTENCY AGENTS

High-potency agents differ from low-potency agents primarily in that high-potency agents cause earlier EPSE but less sedation, orthostatic hypotension, and anticholinergic effects. Because they cause fewer side effects, high-potency agents are generally preferred for initial therapy.²

Haloperidol

Actions and Uses.

Haloperidol, a member of the butyrophenone family, is the prototype of the high-potency neuroleptics. Antipsychotic actions are equivalent to those of chlorpromazine. Principal indications are schizophrenia and acute psychoses. In addition, haloperidol is a preferred drug for Tourette’s syndrome.

Pharmacokinetics. Haloperidol may be administered orally and by IM injection. Oral bioavailability is about 60%. Hepatic metabolism is extensive. Parent drug and metabolites are excreted in the urine.

Adverse Effects.  early ex­trapyramidal reactions (dystonia, parkinsonism, akathisia) occur frequently, whereas sedation, hypotension, and anticholinergic effects are uncommon. The incidence of tardive dyskinesia with haloperidol is the same as with the low-potency drugs. Like chlorpromazine, haloperidol occasionally causes gynecomastia, galactorrhea, and menstrual irregularities. Neuroleptic malignant syndrome, photosensitivity, convulsions, and impotence are rare.

Preparations, Dosage, and Administration. Haloperidol [Haldol] is dispensed in tablets (0.5, 1, 2, 5, 10, and 20 mg) and in a liquid concentrate (2 mg/ml) for oral use. Two injectable forms—haloperidol lactate and haloperidol decanoate—are available for parenteral (IM) administration. Haloperidol lactate is employed for acute therapy. Haloperidol decanoate is a depot preparation used for long-term treatment.

Oral Therapy. The initial dosage for adults is 0.5 to 2 mg taken 2 or 3 times a day. For severe illness, daily doses of up to 100 mg have been employed. Once symptoms have been controlled, the dosage should be reduced to the lowest effective amount.

Intramuscular Therapy. For acute therapy of severe psychosis, haloperidol lactate is administered IM in doses of 2 to 5 mg. Dosing may be repeated at intervals of 30 minutes to 8 hours. Once symptoms are under control, treatment should be changed to oral therapy. Long-term therapy with haloperidol decanoate is discussed later under Depot Preparations.

Del D. Millerab, Nancy C. Andreasen Et Al. Conducted a study on- Comparison of the effects of risperidone and haloperidol on regional cerebral blood flow in schizophrenia.

The result were:- Haloperidol was associated with a significantly greater increase in regional cerebral blood flow in the left putamen and posterior cingulate, and a significantly greater decrease in regional cerebral blood flow in frontal regions compared to risperidone. Risperidone was associated with a significantly greater decrease in regional cerebral blood flow in the cerebellum bilaterally compared to haloperidol.The results show that risperidone and haloperidol have significantly different effects on brain function, which may be related to their differences in efficacy and side effects. Further work is required to more precisely determine the mechanisms by which different antipsychotic medications exert their therapeutic effects on the clinical symptoms and cognition in schizophrenia. These findings emphasize the importance of controlling for both medication status and the individual antipsychotic in neuroimaging studies.⁸

OTHER HIGH-POTENCY AGENTS

Fluphenazine.

 Fluphenazine [Prolixin, Permitil] is a high-potency agent indicated for schizophrenia and other psychotic disorders. The drug belongs to the piperazine subclass of phenothiazines. As with other high-potency agents, the most common adverse effects are early extrapyramidal reactions (acute dystonia, Parkinsonism, akathisia). The risk of tardive dyskinesia is the same as with all other traditional antipsychotics. Effects seen occasionally include sedation, orthostatic hypotension, anticholinergic effects, gynecomastia, galactorrhea, and menstrual irregularities. Neuroleptic malignant syndrome, convulsions, and agranulocytosis are rare.

Fluphenazine is administered orally and by IM injection. For oral use, the drug is available in tablets (1, 2.5, and 5 mg), an elixir (0.5 mg/ml), and a liquid concentrate (5 mg/ml). The liquid concentrate should be diluted with water, fruit juice, or some other suitable fluid—but not with beverages that contain caffeine, tannins (tea), or pectinates (apple juice) because of physical incompatibilities. The initial oral dosage is 2.5 to 10 mg/day given in divided doses every 6 to 8 hours. Daily dosages greater than 3 mg are rarely needed, although some patients may require as much as 30 mg. Once symptoms have been controlled, the dosage should be reduced to the lowest effective amount, typically 1 to 5 mg/day taken as a single dose.

Three injectable preparations are available: fluphenazine (2.5 mg/ml), fluphenazine decanoate (25 mg/ml), and fluphenazine enanthate (25 mg/ml). Fluphenazine itself is used for acute therapy. Fluphenazine enanthate and fluphenazine decanoate are depot preparations vised for long-term therapy . Intramuscular dosages for acute therapy are usually one-third to one-half the oral dosage.

Trifluoperazine.

Trifluoperazine [Stelazine] is a high-potency agent used for schizophrenia and other psychotic disorders. The drug belongs to the piperazine subclass of phenothiazines. The most common adverse effects are early extrapyramidal reactions (dystonia, Parkinsonism, akathisia). Effects seen occasionally include sedation, orthostatic hypotension, anticholinergic effects, gynecomastia, galactorrhea, menstrual irregularities, and tardive dyskinesia. Neuroleptic malignant syndrome, convulsions, and agranulocytosis are rare.

Trifluoperazine is administered orally and by deep IM injection. Three formulations are available: tablets (1, 2, 5, and 10 mg), liquid concentrate (10 mg/ml), and injection (2 mg/ml). Oral dosing is begun at 2 to 5 mg twice daily. Dosage is then increased until an optimal response has been produced, usually with 15 to 20 mg/day. Intramuscular therapy is employed acutely. The usual intramuscular dosage is 1 to 2 mg every 4 to 6 hours as needed.

LONG ACTING ANTIPSYCHOTICS

Low -release preparations are used for patients who need to take antipsychotics medication to prevent relapse but cannot be relied on to take it regularly. These 'depot' preparations include the esters fluphenazine decanoate, flupenthixol decannoate, zuclopenthixol decanoate, haloperidol decanoate, and pipothiazine palmitate. All are given intramuscularly in an oily medium. Zuclopenthixol acetate reaches peak plasma levels within 1-2 days and has a shorter duration of action than other depots. It is used for the immediate control of acute psychosis but its superiority to ordinary intramuscular injections is not established. A slow release injection of risperidone is now available.

Some pharmacokinetic properties of depot antipsychotic drugs
Depot	Time  to  peak plasma     level (days)	Time to steady state (weeks)	Usual   frequency of  administration (weeks)	Equivalent dose (mg)
Fluopenthixol decanoate	7-10	8	2	40
Fluphenazine decanoate	1-2	8	2	25
Haloperidol decanoate	3-9	1	2	100
Pipothiazine palmitate	9-10	8-12	4	5
Zuclopenthixol decanoate	4-7	8	2	200
Risperidone slow release injection	28	6	2	25

Haloperidol decanoate

Haloperidol decanoate is the decanoate ester of the butyrophenone, HALDOL (haloperidol). It has a markedly extended duration of effect. It is available in sesame oil in sterile form for intramuscular {IM} injection. The structural formula of haloperidol decanoate, 4-(4-chlorophenyl)-1 -[4(4-fluorophenyl)-4-oxobutyl]-4 piperidiny]

Haloperidol decanoate is almost insoluble in water (0.01 mg.mL), but is soluble in most organic solvents.

Each mL of HALDOL Decanoate 50 for IM injection contains 50 mg haloperidol (present as haloperidol decanoate 70.52 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative.

INDICATIONS

HALDOL Decanoate 50 and HALDOL Decanoate 100 are indicated for the treatment of schizophrenic patients who require prolonged parenteral antipsychotic therapy.

DOSAGE AND ADMINISTRATION

HALDOL Decanotae 50 and HALDOL Decanoate 100 should be administered by deep intramuscular injection. A 21 gauge needle is recommended. The maximum volume per injection site should not exceed 3 mL. DO NOT ADMINISTER INTRAVENOUSLY.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HALDOL Decanote 50 and HALDOL Decanoate 100 are intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy. These patients should be previously stabilized on antipsychotic medication before considering a conversion to haloperidol decanoate. Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection. During dose adjustment or episodes of exacerbation of symptoms of schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting forms of haloperidol.

The starting dose of haloperidol decanoate should be based on the patient's age, clinical history, physical condition, and response to previous antipsychotic therapy. The preferred approach to determining the minimum effective dose is to begin with lower initial doses and to adjust the dose upward as needed.

Fluphenazine Decanoate

Fluphenazine Decanoate is the decanoate ester of a trifluoromethyl phenothiazine derivative. It is highly potent behaviour modifier with a markedly extended duration of effect.

Fluphenazine decanoate injection is available for INI SC use providing 25 mg Fluphenazine decanoate per mL in a sesame oil vehicle with 12 mg benzyl alcohol as a preservative.

Clinical Pharmacology

Fluphenazine Decanoate has activity at all levels of the CNS as well as on multiple organs systems. The mechanism whereby its therapeutic action is exerted is unknown. It has less potentiative effect on CNS depressants and anesthetics than do some of the phinothiazines and appears to be less sedating, and it is less likely produce hypotension

Indications and Usage

Fluphenazine Decanoate injection is a long acting parenteral antipsychotic drug intended for use in the management of patients requiring prolonged parenteral neurolectic therapy. E.g. Chronic Schizophrenics.

Contraindications

Phenothiazines are contramdicated in patients with the suspected subcotical brain damage. It should not be used in patients receiving large doses of Hypnotics and it is contraindicated in comatose or severely depressed states. The presence of blood dyscraisia or liver damage precludes the use of Fluphenazine Decanoate and it is not used in children under 12 years of age and also in patients those who have hyper sensitivity.

Overdoses

Overdoses typically consist of exaggerated DRA side effects. Symptoms and signs include central nervous system (CNS) depression, extrapyramidal symptoms, mydriasis, rigidity, restlessness, decreased deep tendon reflexes, tachycardia, and hypotension. The severe symptoms of overdose include delirium, coma, respiratory depression, and seizures. Haloperidol may be among the safest typical antipsychotics in overdose. After an overdose, the electroencephalogram (EEG) shows diffuse slowing and low voltage. Extreme overdose can lead to delirium and coma, with respiratory depression and hypotension. Life-threatening overdose usually involves ingestion of other CNS depressants, such as alcohol or benzodiazepines.

Activated charcoal, if possible, and gastric lavage should be administered if the overdose is recent. Emetics are not indicated, because the antiemetic actions of DRAs inhibit their efficacy. Seizures can be treated with IV diazepam or phenytoin. Hypotension can be treated with either norepinephrine or dopamine, but not epinephrine.

Laboratory Interferences

Chlorpromazine and perphenazine may cause both false-positive and false-negative results in immunologic pregnancy tests and falsely elevated bilirubin (with reagent test strips) and urobilinogen (with Ehrlich's reagent test) values. These drugs have also been associated with an abnormal shift in results of the glucose tolerance test, although that shift may reflect the effects of the drugs on the glucose-regulating system. Phenothiazines have been reported to interfere with the measurement of 17-ketosteroids and 17-hydroxycorticosteroids and produce false-positive results in tests for phenylketonuria.

Dosage and Clinical Guidelines

Contraindications to the use of DRAs include-

(1) a history of a serious allergic response

(2) The possible ingestion of a substance that will interact with the antipsychotic to induce CNS depression (e.g., alcohol, opioids, barbiturates, and benzodiazepines) or anticholinergic delirium (e.g., scopolamine and possibly phencyclidine [PCP])

 (3) The presence of a severe cardiac abnormality,

(4) A high risk for seizures

(5) The presence of narrow-angle glaucoma or prostatic hypertrophy if a drug with high anticholinergic activity is to be used.

 (6) The presence or a history of tardive dyskinesia.

Antipsychotics should be administered with caution in persons with hepatic disease, because impaired hepatic metabolism can result in high plasma concentrations. The usual assessment should include a CBC with WBC indexes, liver function tests, and an electrocardiogram, especially in women over 40 years of age and men over 30 years of age. The elderly and children are more sensitive to side effects than are young adults, so the dosage of the drug should be adjusted accordingly.

Various patients may respond to widely different dosages of antipsychotics; therefore, no set dosage exists for any given antipsychotic drug. Because tolerance develops to many side effects, it is reasonable clinical practice to begin at a low dosage and increase it as necessary. It is important to remember that the maximal effects of a particular dosage may not be evident for 4 to 6 weeks.

Adjunctive Medications

It is common practice to use DRAs in conjunction with other psychotropic agents, either to treat side effects or further improve symptoms. Most commonly, this involves the use of lithium or other mood stabilizing agents, SSRIs, or benzodiazepines. It was once held that antidepressant drugs exacerbated psychosis in patients with schizophrenia. In all likelihood, this observation involved patients with bipolar disorder who were misdiagnosed as being schizophrenic. Abundant evidence suggests that antidepressants, in fact, lessen symptoms of depression in patients with schizophrenia. In some cases, amphetamines can be added to DRAs if patients remain withdrawn and apathetic.

NURSING MANAGEMENT OF PATIENTS RECEIVING TYPICAL ANTIPSYCHOTICS⁸

Diagnosis

The following nursing diagnoses may be considered for clients receiving antipsychotic therapy:

v ● Risk for other-directed violence related to panic anxiety and mistrust of others.

v ● Risk for injury related to medication side effects of sedation, photosensitivity, reduction of seizure threshold, agranulocytosis, extrapyramidal symptoms, tardive dyskinesia, and neuroleptic malignant syndrome.

v ● Risk for activity intolerance related to medication side effects of sedation, blurred vision, and weakness.

v ● Noncompliance with medication regimen related to suspiciousness and mistrust of others.

Planning/Implementation

The plan of care should include monitoring for the following side effects from antipsychotic medications.

● Dry mouth

*Provide the client with sugarless candy or gum, ice, and frequent sips of water.

*Ensure that client practices strict oral hygiene.

● Blurred vision

*Explain that this symptom will most likely subside after a few weeks.

*Advice client not to drive a car until vision clears.

*Clear small items from pathway to prevent falls.

● Constipation

*Order foods high in fiber; encourage increase in physical activity and fluid intake if not contraindicated.

● Urinary retention

*Instruct the client to report any difficulty urinating; monitor intake and output.

● Nausea; GI upset

*Tablets or capsules may be administered with food to minimize GI upset.

*Concentrates may be diluted and administered with fruit juice or other liquid; they should be mixed immediately before administration.

● Skin rash

*Report appearance of any rash on skin to physician.

*Avoid spilling any of the liquid concentrate on skin; contact dermatitis can occur with some medications.

● Sedation

*Discuss with the physician the possibility of administering the drug at bedtime.

*Discuss with the physician a possible decrease in dosage or an order for a less sedating drug.

*Instruct client not to drive or operate dangerous equipment while experiencing sedation.

● Orthostatic hypotension

*Instruct the client to rise slowly from a lying or sitting position

*Monitor blood pressure (lying and standing) each shift; document and report significant changes.

● Photosensitivity

*Ensure that the client wears a protective sun block lotion, clothing, and sunglasses while spending time outdoors.

● Hormonal effects

Ø  ● Decreased libido, retrograde ejaculation, gynecomastia (men)

*Provide an explanation of the effects and reassurance of reversibility. If necessary, discuss with the physician the possibility of ordering alternate medication.

Ø  ● Amenorrhea (women)

*Offer reassurance of reversibility; instruct the client to continue use of contraception, because amenorrhea does not indicate cessation of ovulation.

Ø  ● Weight gain

*Weigh client every other day; order a calorie controlled diet; provide an opportunity for physical exercise; provide diet and exercise instruction.

● ECG Changes.

 ECG changes, including prolongation of the QT interval, are possible with most of the antipsychotics. This is particularly true with ziprasidone (Geodon). Caution is advised in prescribing this medication to individuals with history of arrhythmias. Conditions that produce hypokalemia and/or hypomagnesemia, such as diuretic therapy or diarrhea, should be taken into consideration when prescribing. Routine ECG should be taken before initiation of therapy and periodically during therapy.

*Monitor vital signs every shift.

*Observe for symptoms of dizziness, palpitations, syncope, or weakness.

● Reduction of seizure threshold

*Closely observe clients with history of seizures

● Agranulocytosis

*Relatively rare with most of the antipsychotic drugs. It usually occurs within the first 3 months of treatment. Observe for symptoms of sore throat, fever, malaise. A complete blood count should be monitored if these symptoms appear.

● Extrapyramidal symptoms (EPS)

*Observe for symptoms and report; administer antiparkinsonian drugs, as ordered

Ø  ● Pseudoparkinsonism (tremor, shuffling gait, drooling, rigidity)

*Symptoms may appear 1 to 5 days following initiation of antipsychotic medication; occurs most often in women, the elderly and dehydrated clients.

Ø  ● Akinesia (muscular weakness)

*Same as for pseudoparkinsonism.

Ø  ● Akathisia (continuous restlessness and fidgeting)

*This occurs most frequently in women; symptoms may occur 50 to 60 days following initiation of therapy.

Ø  ● Dystonia (involuntary muscular movements [spasms] of face, arms, legs, and neck)

*This occurs most often in men and in people younger than 25 years of age.

Ø  ● Oculogyric crisis (uncontrolled rolling back of the eyes)

*This may appear as part of the syndrome described as dystonia. It may be mistaken for seizure activity. Dystonia and oculogyric crisis should be treated as an emergency situation. The physician should be contacted and intravenous or intramuscular benztropine mesylate (Cogentin) is commonly administered. Stay with the client and offer reassurance and support during this frightening time.

Ø  ● Tardive dyskinesia (bizarre facial and tongue movements, stiff neck, and difficulty swallowing)

*All clients receiving long-term (months or years) antipsychotic therapy are at risk.

*The symptoms are potentially irreversible.

*The drug should be withdrawn at the first sign, which is usually vermiform movements of the tongue; prompt action may prevent irreversibility.

Ø  ● Neuroleptic malignant syndrome (NMS)

*Symptoms include severe Parkinsonian muscle rigidity, hyperpyrexia up to 107⁰F, tachycardia, tachypnea, fluctuations in blood pressure, diaphoresis, and rapid deterioration of mental status to stupor and coma.

*This is a rare, but potentially fatal, complication of treatment with neuroleptic drugs. Routine assessments should include temperature and observation for parkinsonian symptoms.

     CLIENT/FAMILY EDUCATION
 Use caution when driving or operating dangerous machinery. Drowsiness and dizziness can occur.

     Not stop taking the drug abruptly after long-term use. To do so might produce withdrawal symptoms, such as nausea, vomiting, dizziness, gastritis, headache, tachycardia, insomnia, tremulousness.

     Use sunblock lotion and wear protective clothing when spending time outdoors. Skin is more susceptible to sunburn, which can occur in as little as 30 minutes.

     Report weekly (if receiving clozapine therapy) to have blood levels drawn and to obtain a weekly supply of the drug.

      Report the occurrence of any of the following symptoms to the physician immediately: sore throat, fever, malaise, unusual bleeding, easy bruising, persistent nausea and vomiting, severe headache, rapid heart rate, difficulty urinating, muscle twitching, tremors, darkly colored urine, excessive urination, excessive thirst, excessive hunger, weakness, pale stools, yellow skin or eyes, muscular incoordination, or skin rash.

      Rise slowly from a sitting or lying position to prevent a sudden drop in blood pressure.

      Take frequent sips of water, chew sugarless gum, or suck on hard candy, if dry mouth is a problem. Good oral care (frequent brushing, flossing) is very important.

      Consult the physician regarding smoking while on neuroleptic therapy. Smoking increases the metabolism of neuroleptics, requiring an adjustment in dosage to achieve a therapeutic effect.

      Dress warmly in cold weather, and avoid extended exposure to very high or low temperatures. Body temperature is harder to maintain with this medication.

      Not drink alcohol while on neuroleptic therapy. These drugs potentiate each other’s effects.

      Not consume other medications (including over-the counter products) without the physician’s approval.

     Many medications contain substances that interact with neuroleptics in a way that may be harmful.

      Be aware of possible risks of taking neuroleptics during pregnancy. Safe use during pregnancy and lactation has not been established. Neuroleptics are thought to readily cross the placental barrier; if so, a fetus could experience adverse effects of the drug. Inform the physician immediately if pregnancy occurs, is suspected, or is planned.

     Be aware of side effects of neuroleptic drugs. Refer to written materials furnished by health care providers for safe self-administration.

      Continue to take the medication, even if feeling well and as though it is not needed. Symptoms may return if medication is discontinued.

      Carry a card or other identification at all times describing medications being taken.

BIBLIOGRAPHY

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2)      Gelder Michel, Harrison Paul , Cowen Philip (2006) Shorter Oxford Text book of Psychiatry , Fifth edition, Oxford university press, New Delhi, Pp 518 – 565

3)      Vyas J.N , Ahuja (1999), Text book  of Post Graduate  Psychiatry, Vol. II,  Second edition , Jaypee brothers , New Delhi ,Pp  737-  772

4)      Spencer   et al (1993) , Clinical Pharmacology  &  Nursing management ,fourth edition , J. B Lippincott company , Philadelphia , Pp  494 – 527

5)      Anne Collins  (1995)  Clinical Drug  Therapy, Fourth edition , J.B Lippincott  company, Philadelphia, Pp 81 – 143

6)      Lehne Richard (1998) Pharmacology  for  Nursing care,  Third edition, W.B Saunders company, Philadelphia , Pp 279 – 335

7)     MARY C. TOWNSEND, Essentials of Psychiatric Mental Health Nursing Concepts of Care in Evidence-Based Practice, 4^th edn, 2008 F. A. Davis Company pp 237-261

8)      Kenneth V Iserson , Parenteral chlorpromazine treatment of migraine

http://www.annemergmed.com/article/S0196-0644%2883%2980251-0/abstract

9)      Del D. Millerab, Nancy C. Andreasen Et Al. Comparison of the effects of risperidone and haloperidol on regional cerebral blood flow in schizophrenia

URL: http://www.biologicalpsychiatryjournal.com/article/S0006-3223(00)01001-5

http://onlinelibrary.wiley.com/journal/10.1002/%28ISSN%291099-1166