Extrapyramidal motor effects

A. Neuroleptics Antipsychotic potency, sedative, and extrapyramidal motor effects... 

Parkinsonian effects The inhibitory effects of dopaminergic neurons are normally balanced by the excitatory actions of cholinergic neurons. Blocking dopamine receptors alters this balance, causing a relative excess of cholinergic influence and resulting in extrapyramidal motor effects. 

Reith, 1988), and the extensive literature which suggests that cocaine s reinforcing effects are mediated by increases in extracellular dopamine levels in the mesolim-bic dopamine system (Ritz et al., 1987 Koob and Bloom, 1988 Johanson and Fischman, 1989 Kuhar et al., 1991 Woolverton and Johnson, 1992). Dopamine receptor antagonists have been evaluated for their potential utility in treating cocaine abuse (Mello and Negus, 1996) but such agents produce extrapyramidal motor effects and other unwanted effects that complicate their use in the treatment of cocaine dependence. 

The action of the phenothiazines on the extrapyramidal system is now well recognized and a source of concern and at times alarm when individuals develop bizarre extrapyramidal motor effects. Fortunately, these effects soon wear off with cessation of the drug. 

A number of case studies have reported induction of extrapyramidal motor effects in patients following severe anti-ChE intoxication (Muller-Vahl et a ., 1999 Shahar and Andraws, 2001 Arima et ai, 2003 Brahmi et ai, 2004). Joubert and Joubert (1988) reported two OP poisoning cases (unspecified toxicants) with choreiform movements. One patient exhibited choreiform movements in all limbs, but these were more extensive in the arms. Five months after exposure, the patient was depre.ssed, listless, and had episodic grimacing and chorea. The movement disorder improved with halopcridol therapy. The other patient had... 

Chlorpromazine had been shown to produce a tranquil state in animals and since it had a similar effect in humans it became known as a major tranquiliser but the term is rarely used today. Sometimes the drugs used to treat schizophrenia are called anti-psychotics but more commonly neuroleptics. Leptic means to activate (take hold of) and in animals these compounds produce a state of maintained motor tone known as catalepsy. This is an extrapyramidal effect and in schizophrenics the neuroleptics can cause a number of extrapyramidal side-effects (EPSs) including Parkinsonism. The new term neuroleptic is unsatisfactory as a description of clinically useful drugs. It really describes a condition (catalepsy) seen in animals and is more indicative of a compound s ability to produce EPSs than to treat schizophrenia. Antipsychotic is more descriptive but could imply a more general efficacy in psychoses than is the case. It would seem more appropriate to call a drug that is used to treat schizophrenia an antischizophrenic just as we use the terms antidepressant or antiepileptic irrespective of how the drug works. Despite such personal reservations, the term neuroleptic will be used in this text. 

Extrapyramidal side effects These are caused by antipsychotic drugs. They are characterised by motor and postural disturbances, of which the most serious is late-onset tardive dyskinesia. 

Non-motor signs of the disorder are also treatable with symptomatic medications. The frequent mood disorder can be treated with standard antidepressants, including tricyclics (such as amitryptiline) or serotonin reuptake inhibitors (SSRIs, such as fluoxetine or sertraline). This treatment is not without risks in these patients, as it may trigger manic episodes or may even precipitate suicide. Anxiety responds to benzodiazepines, as well as to effective treatment of depression. Long-acting benzodiazepines are favored over short-acting ones because of the lesser abuse potential. Some of the behavioral abnormalities may respond to treatment with the neuroleptics as well. The use of atypical neuroleptics, such as clozapine is preferred over the typical neuroleptics as they may help to control dyskinesias with relatively few extrapyramidal side-effects (Ch. 54). 

Side effects include fatigue, insomnia, and altered motor coordination. Parkinsonian side effects and acute dys-tonic reactions also have been reported. Metoclopramide stimulates prolactin secretion, which can cause galactorrhea and menstrual disorders. Extrapyramidal side effects seen following administration of the phenothiazines, thioxanthenes, and butyrophenones may be accentuated by metoclopramide. 

SSRIs reduce dopamine cell firing in the substantia nigra through their effects on serotonin input to this nucleus. The net result is that they can cause generally mild extrapyramidal side effects (EPS) (500). The most common are restlessness and tremors. The same mechanism is probably responsible for their interaction with other agents that affect central motor systems. Thus, the SSRIs can potentiate the tremor seen with lithium, as well as EPS caused by antipsychotics, bupropion, and psychostimulants (376, 500). 

Several newer antipsychotic medications have been developed that seem different or atypical, compared with their predecessors. These agents include clozapine (Clozaril), risperidone (Risperdal), and several others listed in Tables 8-1 and 8-2. Although there is some debate about what exactly defines these drugs as atypical, the most distinguishing feature is that they have a much better side-effect profile, including a decreased risk of producing extrapyramidal (motor) side effects.17,45,57... 

One of the more serious problems occurring from the use of antipsychotics is the production of abnormal movement patterns.36,44 Many of these aberrant movements are similar to those seen in patients with lesions of the extrapyramidal system and are often referred to as extrapyramidal side effects. The basic reason that these motor problems occur is because dopamine is an important neurotransmitter in motor pathways, especially in the integration of motor function that takes place in the basal ganglia. Because antipsychotic drugs block CNS dopamine receptors, it makes sense that... 

Adverse effects. Disorders of extrapyramidal motor function with development of pseudo-parkinsonism (p. 188), sedation, depression, stuffy nose, impaired libido, impotence and increased appetite. 

The butyrophenones (prototype haloper-idol) were introduced after the phenothiazines. With these agents, blockade of D2 receptors predominates entirely (p. 235B). Antimuscarinic and antiadrenergic effects are attenuated. The extrapyramidal motor disturbances that result from D2 receptor blockade are, however, preserved and constitute the clinically most important adverse reactions that often limit therapy. 

Qll Other neuroleptic agents include phenothiazines, such as chlorpromazine, promazin and thioridazine, and thioxanthines, such as flupenthixol. The non-specific blockade of dopaminergic receptors afforded by these drugs leads to development of side effects, such as endocrine dysfunction and extrapyramidal motor symptoms. The unwanted antagonism of motor tracts results in extrapyramidal side effects, such as Parkinsonism and tardive dyskinesia. The latter is associated with involuntary movements of the face, limbs and trunk. Chronic neuroleptic therapy can inhibit the release of GABA. This in turn leads to changes in mobility. 

The primary treatment for schizophrenia involves use of antipsychotic medications. These are classified as typical or first generation, and atypical. The atypical antipsycho tics differ from the typical in having relatively less extrapyramidal side effects, such as rigidity, dystonia (muscle spasm), akathi-sia (motor restlessness), and pseudo-Parkinsonian symptoms. 

Patients who are neuroleptic naive (i.e. have never previously taken any antipsychotic agent) should start at the lowest available dosage, such as haloperidol 0.5 mg/day or chlorpromazine 25 mg/ day, in case the patient is particularly susceptible to adverse effects, especially extrapyramidal motor... 

The phenothiazine drugs act by blocking dopamine receptors in the limbic system. Unfortunately, phenothiazines also block dopamine in the striatum, upsetting the balance between dopamine and acetylcholine and resulting in side-effects known as extrapyramidal motor signs. These signs include bradykinesia, muscle... 

Most patients who returned to society were able to function moderately well, but if they stopped their medication their condition deteriorated. Also, CPZ and compounds related to this phenothiazine series produced motoric side effects, including extrapyramidal side effects (EPS) that resemble Parkinson s disease. These symptoms could be severe and developed in up to 90% of patients on typical antipsychotic drugs. This condition often progressed to irreversible tardive dyskinesias, involuntary movements of the limbs and facial muscles that resemble the symptoms of Huntington s disease. In addition, such typical antipsychotics, although they were effective in treating the positive or florid symptoms of schizophrenia, did not ameliorate the negative symptoms of the disease. 

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