Introduction

Neuroleptic-induced extrapyramidal symptoms (EPS) are one of the most troublesome side effects of antipsychotic drug therapy. Its prevalance ranges widely from 2% to 90% (Klett et al, 1972; Sovner & DiMascio, 1978; Casey & Keepers, 1988). In highly vulnerable groups of patients e.g. young men receiving high potency neuroleptics, prevalence may approach 100% (Ayd, 1961; Boyer et al, 1987; Ganzini et al, 1991; Casey, 1992).

Anticholinergic drugs are commonly used as an adjunct to neuroleptics to overcome EPS. Although the efficacy of these agents in the treatment of drug-induced EPS is well established, its use remains controversial. There is still no consensus about the stage of neuroleptic treatment at which anticholinergic treatment should be initiated and the duration for which it should be continued. Several studies have been conducted to determine the effectiveness of anticholinergic drugs as prophylactic agents for prevention of EPS, however, the results remain conflicting and contradictory (Lavin & Rifkin, 1991ab). There is much confusion among clinicians about the appropriate method of treating iatrogenically-induced EPS and the most efficacious method of prescribing anticholinergic agents for its treatment.

Mechanism of action of anticholinergic drugs in neuroleptic-induced EPS Symptoms of Parkinson's disease are believed to result from lowering of dopaminergic synthetic enzymes and metabolites in the basal ganglia (see Hornykiewicz, 1982; Javoy-Agid et al, 1984). The key discovery in the neurochemistry of Parkinson's disease was the demonstration by Ehringer & Hornykiewicz (1960) that the concentration of dopamine in the caudate nucleus and putamen in 2 cases of idiopathic Parkinson's disease and 4 cases of post-encephalitic disease was markedly diminished. There is evidence to suggest that a reciprocal balance exists between dopaminergic and cholinergic activity in the striatum and both dopaminergic and anticholinergic drugs have been found to be useful in the treatment of Parkinson's disease (Bartholini et al, 1973).

Extrapyramidal symptoms induced by neuroleptic administration are believed to result from the same mechanism and the disturbance in balance between the striatal dopaminergic and cholinergic systems as a result of dopaminergic antagonism produced by neuroleptics is believed to be the cause of neuroleptic-induced EPS (Snyder et al, 1974). Thus, the treatment strategy utilized in the treatment of EPS is aimed towards restoring this imbalance.

There are only a few reports in the literature to suggest that use of relatively small doses of levodopa can reverse neuroleptic-induced parkinsonism in schizophrenic patients (Inanga et al, 1972; Ogura et al, 1976; Garfinkel & Stancer, 1976), however, dopaminergic drugs as treatment for neuroleptic-induced parkinsonism have generally been reported to be ineffective or to increase psychiatric symptoms (Fleming et al, 1970; Yaryura-Tabias et al, 1970; Mindham et al, 1977). Moreover, since neuroleptics are thought to produce their therapeutic effect by dopamine antagonism, using drugs that enhance dopaminergic neurotransmission would not be a logical strategy. While in Parkinson's disease both pro-dopaminergic as well as anticholinergic drugs are tried to correct this imbalance (Duvoisin, 1967; Bartholini et al, 1973; Klawans, 1973), EPS secondary to neuroleptic administration is usually corrected with the use of anticholinergic drugs.

Anticholinergic drugs act on muscarinic as well as nicotinic receptors. However, its action on muscarinic sub-group of cholinergic receptors is thought to be responsible for alleviation of EPS. Two types of muscarinic receptors have been identified: M1 and M2. M2 receptors are present peripherally, while M1 receptors are present predominantly in the striatum.

All commonly used anticholinergic drugs cross the blood brain barrier and have greater affinity for M1 receptors than the M2 receptors, although their potency and degree of selectivity of each drug varies for the M1 receptor (see Table I).

Potency and selectivity of some anticholinergic drugs for M1 as compared to M2 receptors in decreasing order of potency and selectivity

The benefit of using a high potency anticholinergic compound or one with high selectivity for M1 receptors in terms of efficacy and adverse effect profile has not been determined, however, a drug with lower affinity for M2 receptors suggests low peripheral side effects (Avissar & Schreiber, 1989), since M2 receptors are predominently present in heart and smooth muscle.

Preparations available (Table II & III)

There is little differentiation between the therapeutic and side effect profile or pharmacokinetics of various commercially available preparations and they differ only slightly in potency, duration of action and sedative effect. Benztropine, biperiden and procyclidine all cause drowsiness, and benztropine may also have a prolonged and cumulative effect. On the other hand, orphenadrine occasionally has been reported to cause euphoria. However, the difference lies in the fact that some patients are found to tolerate (or prefer) one drug over another.

Table II: Usual daily dose of preparations available.

Table III: Pharmacological properties of anticholinergic drugs