Antiparkinsonian medications, including anticholinergic, antihistaminic, benzodiazepines, dopamine agonists, and b-blockers are of importance in the management of extrapyramidal side-effects. They are usually needed with the typical neuroleptic drugs but some patients will require antiparkinsonian treatment with olanzapine, risperidone, or quetiapine. The anticholinergics and the antihistaminics (e.g. diphenhydramine) are used to treat acute dyskinesias and dystonias, pseduoparkinsonian symptoms (tremor, rigidity, bradykinesia, shuffling gait), and akathisia. These agents act centrally in the basal ganglia to block the effects of increased acetylcholine release due to D2-receptor blockade. The most widely used anticholinergic drugs are benztropine, biperiden, procyclidine, and trihexyphenidyl. Benztropine is given in doses of 1 to 8 mg/day usually in divided doses. Biperiden is given in doses of 2 to 24 mg/day in two or three doses. Procyclidine is given in divided doses of 5 to 30 mg/day. Trihexylphenidyl is given in doses of 4 to 30 mg/day, in a single or divided dose.
These agents are competitive antagonists of the five subtypes of muscarinic receptors that have been identified and which are labelled M 1 to M5. They have minimal antagonist effect at nicotinic cholinergic receptors. Blockade of cholinergic receptors on intrastriatal neurones by these agents restores the cholinergic balance, which is disrupted by blockade of D2 dopamine receptors by some antipsychotic agents. Other central effects include impairment of various forms of memory. Elderly patients in particular may develop anticholinergic-induced agitation, irritability, disorientation, hallucinations and delirium because of the natural loss of cholinergic neurones with aging.
These agents have some preference for the central nervous system but some peripheral anticholinergic effects are to be expected. Blockade of vagal tone in the heart produces tachycardia. Other adverse effects include decreased bladder function and urinary retention and decreased bowel motility leading to constipation and impaction. Decreased saliva and bronchial secretion contribute to dry mouth and increased dental caries while decreased sweating increases the risk of heat stroke. Blockade of muscarinic receptors in the eye cause pupillary dilation and inhibition of accommodation, leading to photophobia and blurred vision. Rarely, narrow-angle glaucoma may ensue. The muscarinic receptors in the basal ganglia are predominantly M 2 whereas those in the periphery are M1. The rank order of the anticholinergic drugs for relative selectivity for the M 2 receptor is biperiden, procycliden, trihexylphenidyl, and benztropine. All these agents can cause dry mouth, blurred vision, urinary retention, constipation and increased intraocular pressure. They may cause anticholinergic delirium in elderly patients or after taking high doses. Biperidine is less likely to cause peripheral anticholinergic effects. Benztropine, biperiden, and trihexyphenidyl may cause euphoria because of their ability to inhibit dopamine reuptake and may be subject to abuse.
The anticholinergic drugs or the antihistamine diphenhydramine are given intramuscularly for the treatment of acute dystonic reactions. They are usually effective within minutes and may have to be repeated. It is not usually necessary to prescribe an anticholinergic following a dystonic reaction. These agents should not be given prophylactically unless it is well established that the patient generally will have extrapyramidal side-effects at the dose of antipsychotic which is being started. If akathisia or parkinsonism develops following treatment with a typical neuroleptic drug, the first consideration should be whether to continue to use the offending agent and drop the dosage or to substitute an atypical antipsychotic drug. If decreasing the dose of antipsychotic drugs does not suffice, substituting an atypical antipsychotic drug is clearly the recommended choice since it avoids all the unpleasant side-effects of the anticholinergic agents. Clozapine has the least likelihood of causing extrapyramidal side-effects, followed by olanzapine and quetiapine, with the greatest likellihood being for risperidone.
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