| older and new drugs comparison | Older drugs have high affinity for dopamine D2 receptors, whereas newer antipsychotic drugs have greater affinity for serotonin 5-HT2 receptors. Unfortunately, protracted therapy (years) is often needed and can result in severe toxicity in some patients. In bipolar affective disorder, although lithium has been the mainstay of treatment for many years, the use of newer antipsychotic agents and of several antiseizure drugs is increasing |
| classification | The major chemical subgroups of older antipsychotic drugs are the phenothiazines (eg, chlorpromazine, thioridazine, fluphenazine), the thioxanthenes (eg, thiothixene), and the butyrophenones (eg, haloperidol).First-generation antipsychotics are more likely to be associated with movement disorders
Newer second generation drugs of varied heterocyclic structure are also effective in schizophrenia, including clozapine, loxapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. In some cases, these atypical antipsychotic drugs may be somewhat more effective and less toxic than the older drugs. However, they are much more costly than the older drugs, most of which are prescribed generically. |
| pharmacokinetics | The antipsychotic drugs are well absorbed when given orally, and because they are lipid soluble, they readily enter the central nervous system (CNS) and most other body tissues. Some metabolites are active. Many are bound extensively to plasma proteins. After oral administration showing increased absorption with food are ziprasidone and paliperidone. These drugs require metabolism by liver enzymes particularly by CYP2D6, CYP1A2, and CYP3A4 isoenzymes before elimination and have long plasma half-lives that permit once-daily dosing. In some cases, other drugs that inhibit cytochrome P450 enzymes can prolong the half-lives of antipsychotic agents. |
| formulations | Fluphenazine decanoate, haloperidol decanoate, risperidone microspheres, paliperidone palmitate, and olanzapine pamoate are long-acting injectable (LAI) formulations of antipsychotics that are administered via deep gluteal intramuscular injection or deltoid injection. These formulations have a therapeutic duration of action of up to 2 to 4 weeks and, therefore, are often used to treat outpatients and individuals who are noncompliant with oral medications.However, patients may still develop EPS, but the risk of EPS is lower with these LAI formulations compared to their respective oral formulations. |
| tolerance and dependance | The antipsychotic drugs produce some tolerance but little physical dependence. |
| tranquilizer and behaviour control use | The antipsychotic drugs can be used as tranquilizers to manage agitated and disruptive behavior, secondary to other disorders. Antipsychotics are used in combination with narcotic analgesics for treatment of chronic pain with severe anxiety. Also, risperidone and aripiprazole are now approved for the management of the disruptive behavior and irritability secondary to autism. |
| dopamine hypothesis mechanism | 1. Dopamine hypothesis—The dopamine hypothesis of schizophrenia proposes that the disorder is caused by a relative excess of functional activity of the neurotransmitter dopamine in specific neuronal tracts in the brain.First, many antipsychotic drugs block brain dopamine receptors (especially D2 receptors). Second, dopamine agonist drugs (eg, amphetamine, levodopa) exacerbate schizophrenia. Third, an increased density of dopamine receptors has been detected in certain brain regions of untreated schizophrenics. The dopamine hypothesis of schizophrenia is not fully satisfactory because antipsychotic drugs are only partly effective in most patients and many effective drugs have a higher affinity for other receptors, than for D2 receptors.Phencyclidine (PCP) causes a psychotic syndrome but has no effect on dopamine receptors. |
| parkinsonism uses | the newer atypical antipsychotics have also been used to allay psychotic symptoms in patients with Alzheimer’s disease and in parkinsonism. |
| other uses | Chlorpromazine is used to treat intractable hiccups. Although promethazine is not an effective antipsychotic drug, this agent is used in treating pruritus because of its antihistaminic properties. |
| 2. Dopamine receptors— | Each dopamine receptor is G protein-coupled and contains 7 transmembrane domains. The D2 receptor, found in the caudate putamen, nucleus accumbens, cerebral cortex, and hypothalamus, is negatively coupled to adenylyl cyclase. The therapeutic efficacy of the older antipsychotic drugs correlates with their relative affinity for the D2 receptor. Unfortunately, there is also a correlation between blockade of D2 receptors and extrapyramidal dysfunction. |
| other receptor mechanism | Most of the newer atypical antipsychotic agents have higher affinities for other receptors than for the D2 receptor. For example, α adrenoceptor-blocking action correlates well with antipsychotic effect for many of the drugs. The receptor-binding characteristics of the newer antipsychotic drugs have led to a serotonin hypothesis as an alternative to the dopamine hypothesis of the nature of schizophrenia. Most of the atypical drugs cause less extrapyramidal dysfunction than standard drugs. With the exception of haloperidol, all antipsychotic drugs block H1 receptors to some degree. |
| other receptor acting drugs and receptors | Clozapine, a drug with significant D4 and 5-HT2 receptor-blocking actions,D1, muscarinic, and α-adrenergic receptors, but it is also a weak dopamine D2-receptor antagonist. Most of the newer atypical drugs (eg, olanzapine, quetiapine, and risperidone) also have high affinity for 5-HT2A receptors, although they may also interact with D2 and other receptors.Ziprasidone is an antagonist at the D2, 5-HT2A, and 5-HT1D receptors and an agonist at the 5-HT1A receptor. The newer antipsychotic agent aripiprazole is a partial agonist at D2 and 5-HT1A receptors but is a strong antagonist at 5-HT2A receptors. Quetiapine blocks D2 receptors more potently than 5HT2A receptors but is relatively weak at blocking either receptor, and its low risk for EPS may also be related to the relatively short period of time it binds to the D2 receptor. |
| extrapyrimidal toxicity treated by | This toxicity may be reversed by a decrease in dose and may be antagonized by concomitant use of muscarinic blocking agents. extrapyramidal effects are minimized by administration of an anticholinergic drug, such as benztropine. The therapeutic trade-off will be fewer EPS in exchange for the side effect of muscarinic-receptor blockade. [Note: Sometimes,the parkinsonian symptoms and akathisias persist despite the use of anticholinergic drugs.] Akathisia may respond better to β blockers or benzodiazepines rather than anticholinergic medications. |
| neurologic toxic effect appearing time | The maximal risk of appearance of the movement disorders is time and dose dependent, with dystonias occurring within a few hours to days of treatment, followed by akathisias occurring within days to weeks. Parkinson-like symptoms of bradykinesia, rigidity, and tremor usually occur within weeks to months of initiating treatment. Tardive dyskinesia, which can be irreversible, may occur after months or years of treatment. |
| dopaminergic tracts | Dopaminergic tracts in the brain include the mesocortical-mesolimbic pathways (regulating mentation and mood), nigrostriatal tract (extrapyramidal function), tuberoinfundibular pathways (control of prolactin release), and chemoreceptor trigger zone (emesis). |
| effect on dopaminergic tracts | Mesocortical-mesolimbic dopamine receptor blockade presumably underlies antipsychotic effects, and a similar action on the chemoreceptor trigger zone leads to the useful antiemetic properties of some antipsychotic drugs. Adverse effects resulting from receptor blockade in the other dopaminergic tracts, a major problem with older antipsychotic drugs, include extrapyramidal dysfunction and hyperprolactinemia. Note that almost all antipsychotic agents block both α1 and histamine H1 receptors to some extent. |
| newer drugs affect on shizophrenia | Newer atypical drugs are reported to improve some of the negative symptoms of schizophrenia, including emotional blunting, social withdrawal, and lack of motivation ambivalence, and reduced ability to relate to people The “negative” symptoms, such as blunted affect, anhedonia, apathy, and impaired attention, as well as cognitive impairment, are not as responsive to therapy, particularly with the first-generation antipsychotics. Many second-generation agents, such as clozapine, ameliorate the negative symptoms to some extent. |
| treatment of schizophrenia | Antipsychotic drugs reduce some of the positive symptoms of schizophrenia, including hyperactivity, bizarre ideation, hallucinations, and delusions. Overall efficacy of the antipsychotic drugs is, for the most part, equivalent in terms of the management of the floridly psychotic forms of the illness, although individual patients may respond best to a specific drug. However, clozapine is effective in some schizophrenic patients resistant to treatment with other antipsychotic drugs. ll of the antipsychotic drugs can reduce the hallucinations and delusions associated with schizophrenia (the so-called “positive” symptoms) by blocking dopamine receptors in the mesolimbic system of the brain.All of the drugs also have a calming effect and reduce spontaneous physical movement. In contrast to the (CNS) depressants, such as barbiturates, the antipsychotics do not depress the intellectual functioning of the patient as much, and motor coordination difficulties are minimal. The antipsychotic effects usually take several days to weeks to occur, suggesting that the therapeutic effects are related to secondary changes in the corticostriatal pathways. |
| older drugs effect on schizophrenia | The first-generation antipsychotics are most effective in treating positive symptoms of schizophrenia (delusions, hallucinations, thought processing, and agitation). Older drugs are still commonly used, partly because of their low cost compared with newer agents. However, none of the traditional drugs has much effect on negative symptoms of schizophrenia. |
| mania use | The newer antipsychotic drugs are often used with lithium in the initial treatment of mania. Several second generation drugs are approved for treatment of acute mania; two of these (aripiprazole and olanzapine) are approved for maintenance treatment of bipolar disorder. |
| antiemetic use | With the exception of thioridazine and aripiprazole most phenothiazines have antiemetic actions; prochlorperazine is promoted solely for this indication. H1-receptor blockade, most often present in short side-chain phenothiazines, provides the basis for their use as antipruritics and sedatives and contributes to their antiemetic effects., most of the antipsychotic drugs have antiemetic effects that are mediated by blocking D2-dopaminergic receptors of the chemoreceptor trigger zone of the medulla. |
| use in tourettes | The antipsychotic drugs are also used in the management of psychotic symptoms of schizoaffective disorders, in Gilles de la Tourette syndrome, and for management of toxic psychoses caused by overdosage of certain CNS stimulants. Molindone is used mainly in Tourette’s syndrome; it is rarely used in schizophrenia. Pimozide is primarily indicated for treatment of the motor and phonic tics of Tourette disorder. However, risperidone and haloperidol are also commonly prescribed for this tic disorder. |
| reversible neurologic effect extrapyrimidal etc | Dose-dependent extrapyramidal effects include a Parkinson-like syndrome with bradykinesia, rigidity, and tremor. Extrapyramidal toxicity occurs most frequently with haloperidol and the more potent piperazine side-chain phenothiazines (eg, fluphenazine, trifluoperazine). Parkinsonism occurs infrequently with clozapine and is much less common with the newer drugs. Other reversible neurologic dysfunctions that occur more frequently with older agents include akathisia and dystonias; these usually respond to treatment with diphenhydramine or muscarinic blocking agents. |
| 2. Tardive dyskinesias— | This important toxicity includes choreoathetoid movements of the muscles of the lips and buccal cavity and may be irreversible. Tardive dyskinesias tend to develop after several years of antipsychotic drug therapy but have appeared as early as 6 mo. tardive dyskinesia may be attenuated temporarily by increasing neuroleptic dosage; this suggests that tardive dyskinesia may be caused by dopamine receptor sensitization as a compensatory response to long-term dopamine-receptor blockade This makes the neuron supersensitive to the actions of dopamine, and it allows the dopaminergic input to this structure to overpower the cholinergic input, causing excess movement in the patient. Patients display involuntary movements, including bilateral and facial jaw movements and “fly-catching” motions of the tongue. |
| tardive dyskinesia treatment | Antimuscarinic drugs that usually ameliorate other extrapyramidal effects generally increase the severity of tardive dyskinesia symptoms. There is no effective drug treatment for tardive dyskinesia. Switching to clozapine does not exacerbate the condition. A prolonged holiday from antipsychotics may cause the symptoms to diminish or disappear within a few months. However, in many individuals, tardive dyskinesia is irreversible and persists after discontinuation of therapy. |
| 3. Autonomic effects— | Autonomic effects result from blockade of peripheral muscarinic receptors and α adrenoceptors and are more difficult to manage in elderly patients. Tolerance to some of the autonomic effects occurs with continued therapy. Of the older antipsychotic agents, thioridazine has the strongest autonomic effects and haloperidol the weakest. Clozapine and most of the atypical drugs have intermediate autonomic effects. |
| atropine like effects | Atropine-like effects (dry mouth, constipation, urinary retention, and visual problems) are often pronounced with the use of thioridazine and phenothiazines with aliphatic side chains (eg, chlorpromazine). These effects also occur with clozapine and most of the atypical drugs but not with ziprasidone or aripiprazole. Postural hypotension caused by α blockade is a common manifestation of many of the older drugs, especially phenothiazines. In the elderly, measures must be taken to avoid falls resulting from postural fainting. The atypical drugs, especially clozapine and ziprasidone, also block α receptors and can cause orthostatic hypotension. |
| cns effects | CNS effects from block of M receptors may include a toxic confusional state similar to that produced by atropine and the tricyclic antidepressants. |
| phenothiazines | Failure to ejaculate is common in men treated with the phenothiazines. |
| 4. Endocrine and metabolic effects— | Endocrine and metabolic effects include hyperprolactinemia, gynecomastia, the amenorrhea-galactorrhea syndrome, and infertility. Most of these adverse effects are predictable manifestations of dopamine D2 receptor blockade in the pituitary; dopamine is the normal inhibitory regulator of prolactin secretion. Elevated prolactin is prominent with risperidone. Significant weight gain and hyperglycemia due to a diabetogenic action occur with several of the atypical agents, especially clozapine and olanzapine. These effects may be especially problematic in pregnancy. Aripiprazole and ziprasidone have little or no tendency to cause hyperglycemia, hyperprolactinemia, or weight gain. |
| 5. Neuroleptic malignant syndrome— | Patients who are particularly sensitive to the extrapyramidal effects of antipsychotic drugs may develop a malignant hyperthermic syndrome. The symptoms include muscle rigidity, impairment of sweating, hyperpyrexia, and autonomic instability, which may be life threatening. Treatment necessitates discontinuation of the antipsychotic agent and supportive therapy. Drug treatment involves the prompt use of dantrolene, diazepam, bromocriptine and dopamine agonists The antipsychotics depress the hypothalamus, affecting thermoregulation it is characterized by muscle rigidity, fever, altered mental status and stupor, unstable blood pressure, and myoglobinemia. |
| extrapyrimdal effects of different drugs | Those drugs that exhibit strong anticholinergic activity, such as thioridazine, show fewer extrapyramidal disturbances, because the cholinergic activity is strongly dampened. This contrasts with haloperidol and fluphenazine, which have low anticholinergic activity and produce extrapyramidal effects more frequently because of the preferential blocking of dopaminergic transmission without the blocking of cholinergic activity. |
| sedation effect | This is more marked with phenothiazines (especially chlorpromazine) than with other antipsychotics; this effect is usually perceived as unpleasant by nonpsychotic persons. Fluphenazine and haloperidol are the least sedating of the older drugs; aripiprazole appears to be the least sedating of the newer agents. |
| visual and cvs toxicities | Visual impairment caused by retinal deposits has occurred with thioridazine; at high doses, this drug may also cause severe conduction defects in the heart resulting in fatal ventricular arrhythmias. Most of the atypicals, especially quetiapine and ziprasidone, prolong the QT interval of the electrocardiogram (ECG). thoridizaine and ziprasidone toxicity is thus difficult to treat |
| clozapine adverse effect | Clozapine causes a small but important (1–2%) incidence of agranulocytosis and blood counts must be monitored; at high doses the drug has caused seizures. |
| overdose toxicity | Poisoning with antipsychotics other than thioridazine is not usually fatal, although the FDA has warned of an increased risk of death in elderly patients with dementia. Hypotension often responds to fluid replacement. Most neuroleptics lower the convulsive threshold and may cause seizures, which are usually managed with diazepam or phenytoin. |
| drowsiness effects | Drowsiness occurs due to CNS depression and antihistaminic effects, usually during the first few weeks of treatment. Confusion sometimes results. |
| lithium use | Lithium is used for acute-phase illness and for prevention of recurrent manic and depressive episodes. |
| lithuium pharmacokinetics | Lithium is absorbed rapidly and completely from the gut. The drug is distributed throughout the body water and cleared by the kidneys at a rate one fifth that of creatinine. The half-life of lithium is about 20 h. Plasma levels should be monitored, especially during the first weeks of therapy, to establish an effective and safe dosage regimen. For acute symptoms, the target therapeutic plasma concentration is 0.8–1.2 mEq/L and for maintenance 0.4–0.7 mEq/L. Plasma levels of the drug may be altered by changes in body water. Dehydration, or treatment with thiazides, (NSAIDs), ace inhibitors, and loop diuretics, may result in an increase of lithium in the blood to toxic levels. Caffeine and theophylline increase the renal clearance of lithium. |
| mechanism of action of lithium | The mechanism of action of lithium is not well defined. The drug inhibits several enzymes involved in the recycling of neuronal membrane phosphoinositides. This action may result in depletion of the second messenger source, phosphatidylinositol bisphosphate (PIP2), which, in turn, would decrease generation of (IP3) and (DAG). These second messengers are important in amine neurotransmission, including that mediated by central adrenoceptors and muscarinic receptors. |
| other drugs for mania | Olanzapine and quetiapine are both approved as monotherapy for acute mania.Several antiseizure drugs are used in bipolar disorder. Valproic acid has antimanic effects equivalent to those of lithium and is now often as a first choice in acute illness. Valproic acid may be effective in patients who fail to respond to lithium, and in some instances it has been used in combination with lithium. The antiseizure drugs carbamazepine and lamotrigine are also used both in acute mania and for prophylaxis in the depressive phase. |
| clinical use lithium | Lithium carbonate continues to be used for the treatment of bipolar disorder (manic-depressive disease) although other drugs including valproic acid and carbamazepine are equally effective. Maintenance therapy with lithium decreases manic behavior and reduces both the frequency and the magnitude of mood swings. Antipsychotic agents and/or benzodiazepines are commonly required at the initiation of treatment because both lithium and valproic acid have a slow onset of action. |
| lithium contraindication | Although lithium has protective effects against suicide and self-harm, antidepressant drugs are often used concurrently during maintenance. Note that monotherapy with antidepressants can precipitate mania in bipolar patients. |
| adverse effects lithium | Adverse neurologic effects of lithium include tremor, sedation, ataxia, and aphasia. Thyroid enlargement may occur, but hypothyroidism is rare. Reversible nephrogenic diabetes insipidus occurs commonly at therapeutic drug levels. Edema is a common , acneiform skin eruptions occur; and leukocytosis is always present. |
| adverse effects lithium with regards to pregnancy | The issue of dysmorphogenesis is not settled. The use of lithium during pregnancy is thought to increase the incidence of congenital cardiac anomalies (Ebstein’s anomaly). Recent analyses suggest that the teratogenic risk is low, but in pregnancy it appears to contribute to low Apgar scores in the neonate. Consequently, lithium should be withheld 24–48 h before delivery, and its use is contraindicated in nursing mothers. |
| antipsychotic drugs | The antipsychotic drugs (also called neuroleptics or major tranquilizers) are used primarily to treat schizophrenia, but they are also effective in other psychotic states, including manic states with psychotic symptoms such as grandiosity, paranoia, and hallucinations, and delirium. The use of antipsychotic medications involves a difficult trade-off between the benefit of alleviating psychotic symptoms and the risk of wide variety of troubling adverse effects. Antipsychotic drugs are not curative and do not eliminate the chronic thought disorder, but they often decrease the intensity of hallucinations and delusions and permit the person with schizophrenia to function in a supportive environment. |
| schizophrenia | Schizophrenia is a particular type of psychosis (that is, a mental disorder caused by some inherent dysfunction of the brain). It is characterized by delusions, hallucinations (often in the form of voices), and thinking or speech disturbances. This mental disorder is a common affliction, occurring in about 1 percent of the population. The illness often initially affects people during late adolescence or early adulthood and is a chronic and disabling disorder. Schizophrenia has a strong genetic component and probably reflects some fundamental biochemical abnormality, possibly a dysfunction of the mesolimbic or mesocortical dopaminergic neuronal pathways. |
| low potency and high potency | The first-generation drugs are further classified as “low-potency” or “high-potency,” not to indicate the drugs’ clinical effectiveness, but rather to indicate their affinity for the dopamine D2 receptor |
| refractory patients | Approximately 20% of patients with schizophrenia will have an insufficient response to all first- and secondgeneration antipsychotics. For these patients, clozapine has shown to be an effective antipsychotic with minimal risk of EPS. |
| adverse effect rate anti psychotic | Adverse effects of the antipsychotic drugs can occur in practically all patients and are significant in about 80 percent their therapeutic index is high |
| cautions contraindications anti pshcyotics | Acute agitation accompanying withdrawal from alcohol or other drugs may be aggravated by the antipsychotics. Stabilization with a simple sedative, such as a benzodiazepine, is the preferred treatment. All antipsychotics may lower the seizure threshold and should be used cautiously in patients with seizure disorders. Therefore, the antipsychotics can also aggravate pre existing epilepsy and should be used with caution in patients with epilepsy. |
| maintanance treatment | 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. There has been a greater emphasis in research and practice on identifying and aggressively managing first-episode psychosis to determine the benefits of antipsychotic agents in this population. Low doses of antipsychotic drugs are not as effective as higher-dose maintenance therapy in preventing relapse. The rate of relapse may be lower with second generation drugs |
