Parkinsonism antipsychotic drugs

Extrapyramidal effects usually diminish with a reduction in the dosage of the antipsychotic drug. The primary health care provider may also prescribe an antiparkinsonism drug, such as benztropine (see Chap. 29) to reduce the incidence of Parkinson-like symptoms. 

The answer is c. (Hardman, pp 414-4163) Unwanted pharmacologic side effects produced by phenothiazine antipsychotic drugs (e.g., perphenazine) include Parkinson-like syndrome, akathisia, dystonias, galactorrhea, amenorrhea, and infertility. These side effects are due to the ability of these agents to block dopamine receptors. The phenothiazines also block muscarinic and a-adrenergic receptors, which are responsible for other effects. 

There is an increased risk of sedation and delirium with increased age. There is also an increased risk of antidopaminergic effects such as parkinsonism due to antipsychotic drugs. Many other drugs that pass the blood-brain barrier may cause adverse effects in the elderly. The response of opioids may be increased in the elderly, resulting in oversedation (Turnheim 1998). 

Levodopa is widely used for treatment of all types of parkinsonism except those associated with antipsychotic drug therapy. However, as parkinsonism progresses, the duration of benefit from each dose of levodopa may shorten (wearing-off effect). Patients can also develop sudden, unpredictable fluctuations between mobility and immobility (on-off effect). In a matter of minutes, a patient enjoying normal or nearly normal mobility may suddenly develop a severe degree of parkinsonism. These symptoms are likely due to the... 

Seeman P, Tallerico T. Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 1998 3 123-134. 

Dopamine is the immediate precursor in the synthesis of norepinephrine (see Figure 6-5). Its cardiovascular effects were described above. Endogenous dopamine may have more important effects in regulating sodium excretion and renal function. It is an important neurotransmitter in the central nervous system and is involved in the reward stimulus relevant to addiction. Its deficiency in the basal ganglia leads to Parkinson s disease, which is treated with its precursor levodopa. Dopamine receptors are also targets for antipsychotic drugs. 

In the central nervous system, there are close associations between NT and dopamine systems, and NT may be involved in clinical disorders involving dopamine pathways such as schizophrenia, Parkinson s disease, and drug abuse. Consistent with this, it has been shown that central administration of NT produces effects in rodents similar to those produced by antipsychotic drugs. 

Attention has been focused on dopamine because of its relationship to neurological diseases and to addiction (discussed in Section 10). Dopamine receptors constitute a large family, which are classified into two main subfamilies. The D, subfamily consists of D1a and D1B (D5) receptors and the D2 subfamily of D2, D3, and D4 receptors.763 764 The D, receptors, which are prominent in the prefrontal cortex and also in the striatum, are more abundant than the D2 receptors, which are also present in the striatum and the pituitary and are targets for antipsychotic drugs such as haloperidol (Fig. 30-33).765 The recently discovered and less numerous D3 receptors are present in only a few regions of the brain. However, a deficiency of D3 receptors may also be involved in addiction, schizophrenia, and Parkinson disease.766 767... 

A principal interest in our laboratory is the molecular characterization of CNS receptor sites of the neurotransmitter dopamine (DA, 5). These sites are strongly implicated in the biochemical etiology of schizophrenia and Parkinson s Disease, as well as other diseases of the CNS (50,51). Thus, the rank order of clinical potency of antipsychotic drugs (neuroleptics) correlates with the affinity of these drugs for dopaminergic sites (52,53), It is also well established that Parkinson s disease is directly related to deterioration in dopaminergic neurotransmission in the corpus striatum, which is a brain region rich in dopamine receptor sites (54). The use of L-DOPA, the biosynthetic precursor of dopamine, in treatment of patients with Parkinson s disease is one of the best examples of biochemically directed medical treatment. 

Unfortunately, these drugs—especially the first generation of antipsychotics introduced in the 1950s—have side effects similar to those seen in patients with Parkinson s disease tremors when at rest, reduction of voluntary movement, muscle spasticity and dystonia, or sustained muscle contractions. These symptoms confirm the role of dopamine neurons in the initiation and control of movement. Antipsychotic drugs also block dopamine receptors within a region of the brain that controls... 

Tertiary-amine muscarinic receptor antagonists gain access to the central nervous system and are therefore the anticholinergic drugs used to treat parkinsonism and the extrapyramidal side effects of antipsychotic drugs. Specific agents used primarily for these conditions include benztropine mesylate (Cogentin) and trihexyphenidyl hydrochloride (Artane, others). 

Perhaps because of their anticholinergic effects (cf benztropine, Chapter 28 Pharmacologic Management of Parkinsonism Other Movement Disorders), some of the Hi antagonists have significant acute suppressant effects on the parkinsonism symptoms associated with certain antipsychotic drugs. 

Amoxapine is a metabolite of the antipsychotic drug loxapine and retains some of its antipsychotic action and dopamine receptor antagonism. A combination of antidepressant and antipsychotic actions might make it a suitable drug for depression in psychotic patients. However, the dopamine antagonism may cause akathisia, parkinsonism, amenorrhea-galactorrhea syndrome, and perhaps tardive dyskinesia. 

Occasionally, long-term use of lithium is associated with cogwheel rigidity and a parkinsonian tremor (189). More often than not, concurrent or past treatment with an antipsychotic drug is involved. In a review of SSRI-induced extrapyramidal adverse effects, lithium was listed, but not discussed, as a possible risk factor (190). A review of drug-induced parkinsonism provided references to case reports of lithium s occasionally inducing or exacerbating parkinsonism (191). 

Data from short-term clinical trials (6 weeks) suggest that quetiapine may be useful for the management of psychotic disorders in patients who do not tolerate the adverse effects of the typical antipsychotic drugs or clozapine (3). The most common adverse effects of quetiapine were dizziness, hypotension, somnolence, and weight gain. Raised hepatic enzymes have also been reported. In addition, two patients with idiopathic Parkinson s disease and psychosis were treated with quetiapine for 52 weeks (4). Psychotic symptoms were successfully controlled without worsening of motor disability. 

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