Psychotropic Drug Structure

The Parkinson's-Reversing Breakthrough

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Duration of improvement (years)

Figure 13.6. Relationship between the efficacy of L-dopa treatment and time. It should be noted that patients who fail to show any improvement (<50%) after short-term (< 1 year) treatment with L-dopa are probably not suffering from idiopathic

Parkinsonism.

Non-specific MAO inhibitors such as phenelzine, isocarboxazid or tranylcypromine are contraindicated in patients on L-dopa therapy as they are likely to precipitate hyperpyrexia and hypertension. However, recently the selective MAO-B inhibitor deprenyl (also called selegiline) has been shown to be a useful adjunct to L-dopa therapy. Deprenyl, by preventing the catabolism of dopamine in the basal ganglia, enables a lower dose of dopa to be administered and also appears to delay the onset of the more serious side effects of dopa. There is also experimental evidence to show that deprenyl can prevent the occurrence of the symptoms of Parkinsonism induced by the neurotoxin MPTP (see Chapter 15). There is evidence that MPTP is converted to its active metabolite the 1-methyl-4-phenylpyridinium ion (MPP+) by MAO-B. By inhibiting MAO-B, deprenyl therefore protects the basal ganglia from the degenerative effects of MPP+. The low incidence of the ''cheese effect'' and the synergistic interaction between deprenyl and L-dopa suggest that MAO-B type inhibitors will play an increasingly important role in the management of Parkinsonism in the future.

Dopamine receptor agonists

Because of the side effects commonly associated with L-dopa treatment, a number of directly acting dopamine receptor agonists have been tried in the hope that they may combine therapeutic efficacy with reduced adverse effects. Apomorphine was one of the first drugs to be tried and while it was shown to have some effect on the symptoms of Parkinsonism, its short duration of action and the frequency and severity of its side effects precluded its further use. Of the more recently developed dopamine agonists, the ergolines have received particular attention. These drugs include bromocriptine, pergolide and lisuride. Like apomorphine, these drugs are not specific agonists for the D2 type receptors and all have side effects which are related to their ergot type of structure. Nausea and vomiting are particularly prominent side effects, even at low doses, while psychiatric reactions and postural hypotension of the type associated with L-dopa are also features of the ergolines.

Of the ergolines that have been developed, bromocriptine has received most attention. Since the first report in 1974 of its use as an adjunct to L-dopa therapy, more than a decade of clinical experience with bromocriptine has failed to establish a distinct role for the drug in the treatment of parkinsonism. Experience with the use of bromocriptine alone in newly diagnosed cases is even more limited. Unacceptable adverse reactions are frequent and even in those patients who can tolerate the gastrointestinal side effects the beneficial effects decline rapidly. It seems unlikely that the rapid onset of tolerance to the therapeutic effects is only due to changes in dopamine receptor sensitivity, as L-dopa is generally effective in patients who cease to respond to bromocriptine. It is also of interest that the abnormal involuntary movements which frequently occur following dopa therapy are seldom found after treatment with the ergolines. The reason for this is unknown but may be associated with differences in the action of these drugs on dopamine receptor subtypes. Bromocriptine, for example, acts as a partial agonist at D1 receptors and as a full agonist at D2 receptors. Whether the development of a specific D2 agonist will combine therapeutic efficacy with a reduced frequency of side effects remains to be seen. The structure of some of the ergolines that have been used in the treatment of parkinsonism is shown in Figure 13.7.

Amantadine

This is an antiviral agent which was accidentally discovered to be of some value in the initial treatment of Parkinson's disease. While the precise mechanism of action of this drug is uncertain, there is experimental evidence to show that it increases the release and synthesis of dopamine and inhibits its reuptake, thereby facilitating the action of the neuro-transmitter in those dopaminergic terminals that are still able to function. It has been found that patients soon develop a tolerance to the beneficial effects of the drug, which has largely precluded its long-term use.

Amantadine Parkinson

Figure 13.7. Chemical structure of some ergolines that have been or are currently used in the treatment of Parkinsonism. The outline structure of dopamine is also given to show why these drugs act as dopamine receptor agonists. The extended side chains in lisuride may also account for the action of the drug on 5-HT (particularly 5-HT2) receptors. The hallucinogenic effects of lisuride may be attributed to its action on central 5-HT2 receptors.

Figure 13.7. Chemical structure of some ergolines that have been or are currently used in the treatment of Parkinsonism. The outline structure of dopamine is also given to show why these drugs act as dopamine receptor agonists. The extended side chains in lisuride may also account for the action of the drug on 5-HT (particularly 5-HT2) receptors. The hallucinogenic effects of lisuride may be attributed to its action on central 5-HT2 receptors.

Anticholinergic drugs

These drugs, initially as the crude extract of Atropa belladonna and more recently as specific anticholinergic drugs such as benztropine or biperiden, have been used for over a century to reduce the tremor seen in patients with Parkinsonism. The mechanism of action of these drugs lies in their ability to reduce the functional activity of the excitatory cholinergic system in the basal ganglia; centrally acting anticholinesterases such as physostigmine are known to exacerbate the tremor associated with the disease.

In the past 40 years a wide variety of synthetic and semi-synthetic anticholinergic agents have been developed for their selectivity in blocking muscarinic receptors in the brain (see Figure 13.8 for the structure of some

Mechanism Action Procyclidine

Biperiden hydrochloride

Procyclidine hydrochloride

Figure 13.8. Chemical structure of amantadine and of centrally acting anti-cholinergic agents used in the treatment of Parkinsonism. The antiviral compound amantadine is a dopamine-releasing agent with some anticholinergic activity.

Biperiden hydrochloride

Procyclidine hydrochloride

Figure 13.8. Chemical structure of amantadine and of centrally acting anti-cholinergic agents used in the treatment of Parkinsonism. The antiviral compound amantadine is a dopamine-releasing agent with some anticholinergic activity.

of those in current clinical use), but all are associated to some degree with the typical peripheral anticholinergic effects of blurred vision, dry mouth, urinary retention and constipation. The popularity of benzhexol lies in its additional ability to inhibit striatal dopamine reuptake.

The anticholinergic agents attenuate the tremor associated with Parkinsonism and relieve the muscular rigidity, but have no effect on the akinesia. This suggests that the features of increased tremor and rigidity are the result of disinhibited cholinergic efferent activity, whereas the negative symptoms of reduced motor function correlate with the dopamine deficiency. There is evidence of tolerance development after several years of treatment with these drugs, so that their use is largely restricted to the more acute phase of the disease.

Table 13.3. Drugs used in the treatment of Parkinson's disease

Mechanisms of action

Drugs

L-dopa

Direct-acting dopamine receptor agonists Dopamine releasing agent Monoamine oxidase B inhibitor Centrally acting anticholinergic drugs

Free radical scavengers (of doubtful clinical efficacy)

Levodopa, levodopa+carbidopa, levodopa+ benserazide, levodopa+carbidopa (controlled release formulation), levodopa infusion Apomorphine, bromocriptine, lisuride, pergolide

Amantadine Selegiline (deprenyl)

Benzotropine, trihexyphenidyl, procyclidine Ascorbate; tocopherol

In addition, antidepressants are sometimes necessary to reduce the depressive symptoms which frequently occur in these patients.

It must be stressed that elderly patients are particularly sensitive to the anticholinergic effects of drugs, whether they be tricyclic antidepressants, phenothiazine neuroleptics or central anticholinergics. Such drugs can cause toxic confusional states and impaired memory and intellectual function; these effects are particularly apparent following long-term therapy. For this reason, such drugs should only be used sparingly in the elderly and then only when other therapeutically effective agents cannot be used.

Table 13.3 summarizes the drugs which have been used to treat the symptoms of Parkinson's disease.

Limitations in the use of L-dopa in the treatment of parkinsonism: the ''on-off'' phenomenon

The combination of L-dopa with a peripheral dopa decarboxylase inhibitor is generally considered to be the most effective therapy for idiopathic parkinsonism. A major controversy concerns the timing of the initiation of drug treatment. Some investigators favour delaying treatment for as long as possible since there is evidence that drug-induced dyskinesias and fluctuations in response to treatment (the ''on-off'' phenomenon) are related to the early initiation of drug treatment. However, there is increasing clinical evidence that the dyskinesias and fluctuation in treatment response are a reflection of the degenerative changes caused by the disease. It has also been shown that there is a reduction in the mortality and a slower progression in the severity of the disease when treatment is initiated relatively soon after the disease has been diagnosed.

Two main phases of treatment with L-dopa have been distinguished. The initial induction phase lasts several weeks and is followed by the maintenance phase. During the induction phase the daily dose of L-dopa should be increased slowly to minimize the likelihood of side effects. However, following 2-5 years' successful therapeutic control of the symptoms, the dyskinesias and abnormal involuntary movements often occur. Such changes are attributed to striatal dopamine receptor super-sensitivity, possibly occurring as a consequence of denervation of the dopaminergic tracts in the nigrostriatal area. When they occur, the dyskinesias are superimposed on the waxing and waning of the response to treatment, and may be associated with the peak therapeutic effect (called ''peak-dose'' dyskinesia). Eventually the patient becomes unable to achieve any degree of mobility without experiencing some involuntary movement. Dietary factors and erratic gastric emptying may further complicate the picture so that the response to L-dopa may seem random and unrelated to the time of administration of the drug. At this stage, the patient may suddenly switch from a state of good therapeutic control to severe parkinsonism (the ''on-off'' effect); such a situation occurs in up to 50% of patients after 5 or more years of treatment and may eventually occur in 90% of patients after more than a decade of treatment.

The fluctuating motor performance can be partly explained by the pharmacokinetics of L-dopa. Most patients have a critical plasma dopa concentration above which the therapeutic effects are apparent. Presumably this reflects the dose necessary to raise the concentration of dopamine in the brain. However, as the degeneration of the nigrostriatal pathway continues, the capacity of dopaminergic neurons to synthesize and store the amine becomes progressively compromised so that the neurons that continue to function are increasingly dependent on the presence of L-dopa for immediate brain dopamine synthesis. Fluctuations in motor performance therefore reflect this dependency on plasma dopa. Thus the beneficial effects of L-dopa decrease with the increasing severity of the motor symptoms, despite the fact that the elimination half-life is relatively uniform throughout the period of treatment. This means that lowering the dose of L-dopa administered in an attempt to reduce the dyskinesia will inevitably lead to a shortened duration of therapeutic effect.

Management of the motor fluctuations has largely been concentrated on attempts to prolong the duration of action of the drug, either by the use of controlled release preparations to obtain ''smooth'' concentration-time curves or by combining dopa with deprenyl or bromocriptine. Long-term (about 16 years) follow-up studies of patients have shown that the mean ''functional'' status of the patient approaches pretreatment levels after 5 years, and by 16 years all surviving patients were functionally less well than at the initiation of therapy. From such studies it may be concluded that

L-dopa does not cure Parkinson's disease but does produce significant relief for many years and still remains the most effective treatment for the illness.

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