Neuroleptics parkinsonism

For CNS aspects of dopamine, agonists and antagonists see Neuroleptics, Parkinsonism. 

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). 

Figure 7.8 Dopamine and motor function. When nigrostriatal dopamine activity is normal so is motor function. Any reduction in this DA activity, as in Parkinson s disease, results in reduced motor activity, i.e. akinesia. By contrast, too much DA activity, as in Huntington s Chorea, produces abnormal motor function, i.e. dyskinesia. The latter may be controlled by neuroleptic drugs (DA antagonists) but they can swing the balance in DA activity sufficiently to produce akinesia (Parkinsonism). DA agonists (and levodopa) may overcome akinesia but can induce DA overactivity and dyskinesia (peak dose effect) (see Chapter 15)...

Chlorpromazine had been shown to produce a tranquil state in animals and since it had a similar effect in humans it became known as a major tranquiliser but the term is rarely used today. Sometimes the drugs used to treat schizophrenia are called anti-psychotics but more commonly neuroleptics. Leptic means to activate (take hold of) and in animals these compounds produce a state of maintained motor tone known as catalepsy. This is an extrapyramidal effect and in schizophrenics the neuroleptics can cause a number of extrapyramidal side-effects (EPSs) including Parkinsonism. The new term neuroleptic is unsatisfactory as a description of clinically useful drugs. It really describes a condition (catalepsy) seen in animals and is more indicative of a compound s ability to produce EPSs than to treat schizophrenia. Antipsychotic is more descriptive but could imply a more general efficacy in psychoses than is the case. It would seem more appropriate to call a drug that is used to treat schizophrenia an antischizophrenic just as we use the terms antidepressant or antiepileptic irrespective of how the drug works. Despite such personal reservations, the term neuroleptic will be used in this text. 

Effects similar to those of the neuroleptics have also been described for other dopamine-blocking agents. Thus, parkinsonism and tardive symptoms may result from use of metoclopramide, a drug which is commonly used to enhance gastric motility, or certain antiemetics, such as perphenazine. 

Drugs that are successful in treating the disease act as dopamine receptor blockers and are known as antipsychot-ics or neuroleptics (e.g. chlorpromazine, haloperidol). Antipsychotic drags reduce some of the symptoms, especially the delusions and hallucinations. A side-effect of the drugs is that they can result in symptoms similar to those seen in patients with Parkinson s disease. This is not surprising, since the hypothesis to explain Parkinson s disease is too low a concentration of dopamine in a specific area of the brain (see below). 

Dopamine antagonist activity is the hallmark of classical neuroleptics. The antihypertensive agents, reserpine (obsolete) and a-methyldopa, deplete neuronal stores of the amine. A common adverse effect of dopamine antagonists or depletors is parkinsonism. 

Dementia with Lewy bodies, Parkinson s disease and neuroleptic sensitivity... 

The dopaminergic system is probably the next most popular contender on account of the continuous bring of mesolimbic neurons during the entire sleep/wake cycle (Chapter 7), and involvement of this system in schizophrenia, Parkinson s disease, and more controversially autism (Chapters 15,17 and 19), together with the actions of neuroleptics (Chapter 11). While not per-... 

The brain stem cholinergic neurons are essential for the regulation of sleep-wake cycles via projections to the thalamus. The cholinergic interneurons in the striatum modulate striatal GABAergic neurons by opposing the effects of dopamine. Increased cholinergic tone in Parkinson s disease and decreased cholinergic tone in patients treated with neuroleptics are examples of an imbalance of these two systems in the striatum (Cala-bresi et al., 2000). 

Other diagnostic indications. A few less well-known diagnostic indications for ECT exist. The use of ECT in patients with Parkinson s disease is receiving greater interest. ECT is an effective treatment for depressions associated with this illness and may also be of benefit for the motor manifestations [see C. H. Kellner et al. 1994 for review]. Other conditions in which the use of ECT may be appropriate include catatonia and the neuroleptic malignant syndrome [Sackeim et al. 1995]. 

Extrapyramidal reactions include parkinsonism, acute muscular dystonias, akathisia, tardive dyskinesia and malignant neuroleptic syndrome. They can also cause hypersensitivity reaction including cholestatic jaundice, skin rash, urticaria, photosensitivity and contact dermatitis. There is also blue pigmentation of skin, lenticular opacities on prolonged use of drug. 

Postmortem studies of patients with idiopathic Parkinson s disease demonstrate cell loss in the striatal system (A-9), directly implicating this tract vis-a-vis the neuroleptic-induced pseudoparkinsonian side effects. The assumption that psychosis is related to the A-10 system is made by exclusion. Evidence also indicates that clozapine may differentially block DA pathways. Specifically, it seems to act on the mesolimbic dopaminergic system (A-10), while being relatively inactive in the striatal system (A-9) however, this remains controversial. Chronic administration of clozapine decreases the firing rate of A-10 mesocortical tract dopamine neurons... 

In the international, multicenter, double-blind trial of olanzapine, the Simpson-Angus Scale and the Barnes Akathisia Scale were used to monitor treatment-emergent EPS. The acute phase was followed by a 52-week, double-blind, maintenance phase, during which there were significantly lower rates of treatment-emergent Parkinsonism and akathisia (p > 0.001), as well as TD (p < 0.003) in comparison with haloperidol (117). These results suggest that olanzapine has a substantially lower propensity than neuroleptics to evoke EPS, and perhaps TD. 

Dopamine is a major neurotransmitter which acts on multiple receptors. It can activate both a and 3 adrenoceptors in addition to acting on specific dopamine receptors. These are widely distributed throughout the CNS and are also present in the renal tubules and renal and mesentric blood vessels, and many dopaminergic drugs are used in the treatment of Parkinson s disease, psychiatric disorders, as antiemetics, and for renal protection. Neuroleptic drugs, such as haloperidol and droperidol, are dopamine receptor antagonists. 

Neuroleptic malignant syndrome D2-blocking antipsychotics Acute severe parkinsonism hypertension, hyperthermia, normal or reduced bowel sounds, onset over 1-3 days Diphenhydramine (parenteral), cooling if temperature is very high, sedation with benzodiazepines... 

AccessMedicine Print Chapter 28. Pharmacologic Management of Parkinsonism Other Movement Disorders Haloperidol, other neuroleptics Sometimes helpful... 

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