Dopamine extrapyramidal symptoms

Extrapyramidal side-effects generally appear with blockade of dopamine D2 receptors in excess of 80%, whereas clinical efficacy in treating psychosis is associated with 60-70% D2 receptor blockade [12]. Recently, a partial agonist for the D2 receptor known as aripiprazole has been developed, which results in approximately 70% antagonism/30% agonism at the D2 receptor. It is an effective antipsychotic, has low risk for extrapyramidal symptoms, and does not cause elevated levels of prolactin as do the full antagonists at D2 receptors. 

Areca may interact adversely with antipsychotic medications (Deahl 1989). Two cases have been reported of schizophrenic patients who were taking neuroleptics and developed severe extrapyramidal symptoms after areca chewing. Given the functional antagonism between dopamine and acetylcholine in the striatum, it is likely that arecoline amplified the dyskinetic effect of neuroleptic medications. 

Most antipsychotics and especially the piperazines and the butyrophenones can cause extrapyra-midal symptoms. Blockade of dopamine receptors mainly in the corpus striatum is held responsible for these extrapyramidal effects. They may become manifest as a variety of clinical symptoms and it should be noted that within 24 8 hours after the beginning of treatment acute dystonic reactions like torticollis, facial grimacing and opisthotonos may occur. Parkinsonism-like symptoms such as bradyki-nesia, rigidity and tremor occur after weeks or months of therapy and are more common in the elderly. Motor restlessness, i.e. akathisia, also mostly occurs not before weeks or months after starting therapy. The tendency of an antipsychotic agent to produce extrapyramidal symptoms appears to be inversely related to its ability to block cholinergic receptors. 

The most troublesome untoward effects of treatment with reserpine involve the CNS. Sedation and depression are the most common, although nightmares and thoughts of suicide also occur. Reserpine treatment, therefore, is contraindicated in patients with a history of severe depression. The occasional report of re-serpine-induced extrapyramidal symptoms, which are similar to those seen in patients with Parkinson s disease, is believed to be a result of dopamine depletion from neurons in the CNS. 

Kapur S, Remington G, Zipursky RB, et al. The D 2 dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms a PET study. Life Sci 1995 57 103-107. 

Metoclopramide is structurally related to orthoclopramide, a procaine derivative, and it can prolong the action of suxamethonium because of competition for cholinesterase. However, its common side effects are similar to those seen with phenothiazine derivatives. In high doses, a range of extrapyramidal symptoms may develop. The anti-emetic effects of metoclopramide are due to two main actions. Centrally, it blocks dopamine in the CTZ and peripherally, it hastens gastric emptying, abolishes irregular intestinal contractions, and increases... 

FIGURE 11 —4. When dopamine 2 receptors are blocked by dopamine 2 antagonists in the postsynaptic projections of the nigrostriatal pathway, it produces disorders of movement, which can appear very much like those in Parkinson s disease. That is why these movements are sometimes called drug-induced parkinsonism. Since the nigrostriatal pathway projects to the basal ganglia, a part of the so-called extrapyramidal nervous system, side effects associated with blockade of dopamine 2 receptors there are sometimes also called extrapyramidal symptoms (EPS). 

FIGURE 11—10. This figure shows what happens to acetylcholine activity when dopamine receptors are blocked. As dopamine normally suppresses acetylcholine activity, removal of dopamine inhibition causes an increase in acetylcholine activity. Thus, if dopamine receptors are blocked, acetylcholine becomes overly active. This is associated with the production of extrapyramidal symptoms (EPS). The pharmacological mechanism of EPS therefore seems to be a relative dopamine deficiency and an acetylcholine excess. 

FIGURE 11 — 11. One compensation for the overactivity of acetylcholine that occurs when dopamine receptors are blocked is to block the acetylcholine receptors with an anticholinergic agent. Thus, anticholinergics overcome excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked by conventional antipsychotics. This also means that extrapyramidal symptoms (EPS) are reduced. 

From a clinical perspective, an atypical antipsychotic, however, is defined in part by the clinical properties that distinguish such drugs from conventional antipsychotics, namely, low extrapyramidal symptoms and efficacy for negative symptoms. By understanding the difference between blocking dopamine D2 receptors alone... 

Parkinson s disease Neurological disorder accompanied by dopamine deficiency. Patients exhibit extrapyramidal symptoms. 

In the in-vitro kinetic experiments, the rates of association (Kon) and dissociation (Kan) of various (labeled) antipsychotic compounds to dopamine D2 receptors were determined. Kapur and Seeman found that antipsychotics substantially differ (almost 1000-fold) in their Koff rate (whereas only 10-fold differences were found in the Kon rate), and that this value is highly correlated with their affinity to D2 receptors. These authors also demonstrated that Koff for clozapine, olanzapine and quetiapine was 1.386 min"1, 0.039 min"1, and 3.013 min"1, respectively, and assumed that the rate of how rapidly they left the receptor was an important mechanism in their atypical antipsychotic action. Indeed, this fully explained the lack of extrapyramidal symptoms (EPS) and hyperprolactinemia and the low risk for tardive dyskinesia [34—36]. In this regard, quetiapine (which has the lowest affinity to D2 receptors) seems to be the most atypical among all tested antipsychotics, followed by clozapine and olanzapine (nevertheless, olanzapine s Koff value is close to those of raclopride and chlorpromazine). 

The effects of cocaine or its withdrawal on neurotransmitter activity have been evaluated in several studies. Although changes in dopaminergic activity appear to be associated with early cocaine abstinence, extrapyramidal symptoms (due to alterations in dopamine functioning) have only infrequently been reported in cocaine users. 

Has atypical antipsychotic properties (i.e., antipsychotic action without a high incidence of extrapyramidal symptoms), especially at low doses, but not a serotonin dopamine antagonist... 

Extrapyramidal symptoms. All classical antipsychotics are capable of producing these effects because they act by blocking dopamine receptors in the nigrostriatal pathway. The result is that some 75% of patients experience extrapyramidal symptoms which may appear shortly after starting the drug or increasing its dose (acute effects), or some time after a particular dose level has been established (tardive effects, see p. 387). 

The neuroleptics produce extrapyramidal side effects due to the blocking of dopamine receptors. In addition to producing a reduction in positive psychotic symptoms by blocking dopamine in the mesolimbic region, they unfortunately produce extrapyramidal symptoms by dopamine blockade in the basal ganglia. There are three types of acute extrapyramidal symptoms Parkinsonian side effects are those that resemble Parkinson s disease, with slowed movements, decreased facial expres-... 

Dopamine Antagonists Block dopamine receptors in the CTZ, preventing nausea and vomiting. Side effects are extrapyramidal symptoms and hypotension. These include ... 

Extrapyramidal Symptoms. Acute ex-trapyramidal symptoms (EPS) consists of drug-induced parkinsonism (DIP), akathisia, and dystonia. Because of a common link to diminished CNS dopamine function at D2 receptors, DIP and idiopathic Parkinson s disease are indistinguishable. As in Parkinson s... 

The principal manifestations of phenothiazine toxicity involve the CNS and cardiovascular system. Signs of CNS toxicity include sedation, coma, respiratory depression (uncommon), seizures, hypothermia or hyperthermia, and extrapyramidal movement disorders (acute dystonia, parkinsonism, akathisia, tardive dyskinesia, and neuroleptic malignant syndrome) the extrapyramidal symptoms result from an imbalance between inhibitory dopamine and... 

Giizey C, Scordo MG, Spina E, et al. Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia associations with dopamine and serotonin receptor and transporter polymorphisms. Eur J Clin Pharmacol 2007 63(3) 233—41. 

Hedenmalm K, Giizey C, Dahl M-L, et al. Risk factors for extrapyramidal symptoms during treatment with selective serotonin reuptake inhibitors, including cytochrome P-450 enzyme, and serotnin and dopamine transporter and receptor polymorphisms. J Clin Psychopharmacol 2006 26 192-7. 

The traditional or typical antipsychotics are dopamine inhibitors that block other neurotransmitters such as acetylcholine, histamine, and norepinephrine. Extrapyramidal symptoms (EPS) are a common side effect with these medications, and the social worker must be able to recognize them. Dystonia is one of the movement problems that may occur, and acute dystonic reactions may present as grimacing, difficulty with speech or swallowing, oculogyric crisis (upward rotation of the eyeballs), muscle spasms of the neck and throat, and extensor rigidity of the back muscles (Carpenter, Conley, Buchanan, 1998). Very often these parkinsonian reactions will occur within the first few days of treatment. It is not uncommon for the client to approach the social worker complaining of a thick or stiff tongue that impairs the ability to speak. 

---