Extrapyramidal side-effects drug treatments

Trihexyphenidyl (Artane) and benztropine (Cogentin) are prescription drugs used in the treatment both of Parkinson s disease and the extrapyramidal side effects produced by neuroleptic medication. They are occasionally abused for their mind-altering properties, which occur at toxic doses (Perry et al. 1978). Abusers often try to obtain these drugs by false representation of extrapyramidal symptoms, which are claimed to result from the use of phenothi-azines or other neuroleptics (Rubinstein 1978). 

The drug was subsequently reintroduced for treatment-resistant or treatment-intolerant patients in the UK and USA in 1990. The drug is completely free of extrapyramidal side effects but has to be monitored for the development of neutropenia and agranulocytosis. Other problems include sialorrhoea, sedation, reduction in seizure... 

Antipsychotic medications, previously referred to as major tranquilizers or neuroleptics, are effective for the treatment of a variety of psychotic symptoms—such as hallucinations, delusions, and thought disorders—regardless of etiology. The term major tranquilizer is a misnomer because sedation is generally a side effect, and not the principal treatment effect. Similarly, the term neuroleptic is based on the neurological side effects characteristic of older antipsychotic drugs, such as catalepsy in animals and extrapyramidal side effects (EPS) in humans. 

Haloperidol is used as an antipsychotic and occasionally for control of acute agitation in the intensive care unit. It is can also be useful in the treatment of phencyclidine abuse. It produces a cataleptic state with little drowsiness and has minimal effects on blood pressure and respiration. It is a long-acting drug with a half-life of about 18 hours. It is available in oral and injectable preparations. In large doses extrapyramidal side effects may occur. 

In clinical studies, remoxipride has been shown to improve both positive and negative symptoms of schizophrenia and may have a place in the treatment of resistant schizophrenic patients. In addition such side effects as the neuroleptic-induced deficit syndrome, sedation and extrapyramidal side effects are apparently absent in patients treated with the drug. 

Regarding the extrapyramidal side effects commonly found after treatment with the "classical neuroleptics, PET studies of schizophrenia patients have shown that such drugs occupy 70-80% of D2 receptors in the basal ganglia at therapeutic doses. It has been calculated that a D2 receptor occupancy in the basal ganglia of approximately 80% carries a high risk that the patient will develop extrapyramidal side effects. Furthermore, Canadian studies have shown that the occurrence of extrapyramidal side effects was a major predictor for the subsequent development of tardive dyskinesia. 

Neuroleptics have been the group of drugs most widely recommended for delusional states. Of the first-generation neuroleptics, the sedative, cognitive impairing and extrapyramidal side effects are likely to be particularly prominent in the elderly. The introduction of the atypical neuroleptics should improve the treatment of these disorders as they are generally better tolerated due to their improved side-effect profile. 

Many earlier reports considered extrapyramidal side effects unavoidable when treating patients with neuroleptics. There appeared to he a parallel between antipsychotic action and the incidence of unwanted neurological effects. However, the development of newer neuroleptics has changed this view. Drugs like clozapine have a high antipsychotic potency and yet produce few neurological problems. It has therefore been proposed that the DA receptors involved in the beneficial actions of neuroleptics in the treatment of psychiatric disorders are situated in mesolimbic areas, such as the nucleus accumbens, whereas the extrapyramidal effects are mediated by striatal receptors. 

Two drugs related to clozapine include the almost identical compound, olanzapine (52), and quetiapine (53)Hoth confer similar antipsychotic profiles and a minimal propensity to elicit extrapyramidal side effects (317, 318). Olanzapine has also found use in the treatment of tardive dyskinesia (319). 

Clozapine, which is associated with higher risk of agranulocytosis and seizures, is indicated (25 mg once or twice daily) only in the management of schizophrenic patients who fail to respond adequately to standard antipsychotic drug treatment. On the other hand, it is relatively free from extrapyramidal side effects such as parkinsonism. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces as inactive demethylated, hydroxylated, and N-oxide derivatives. Clozapine has anticholinergic properties and causes tachycardia, and hence poses a serious risk for a patient with compromised cardiovascular function (see also Table 23). 

The belladonna alkaloids and related muscarinic receptor antagonists have long been used in parkinsonism. These agents can be effective adjuncts to treatment with levodopa see Chapter 20). Muscarinic receptor antagonists also are used to treat the extrapyramidal symptoms that commonly occur as side effects of conventional antipsychotic drug therapy see Chapter 18). Certain antipsychotic drugs are relatively potent muscarinic receptor antagonists, and these cause fewer extrapyramidal side effects. 

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