Haloperidol receptor blocking actions

There is another reason why medications exert multiple effects. For example, an antidepressant that very specifically promotes serotonin neurotransmission and has little or no interaction with other receptor types will still produce multiple effects. How can this be Remember that in different areas of the brain, a single neurotransmitter can assume very distinct roles. When an individual takes a medication that alters the activity of a particular neurotransmitter, it generally does so throughout the brain. Consequently, the dopamine receptor blocking effect of haloperidol (Haldol) reduces hallucinations and paranoia in one brain region but causes upper extremity stiffness through its action in another brain region. 

It also seems plausible that antipsychotic drugs competitively bind with dopamine receptors and block the action of dopamine on corresponding receptor sites, thus lowering psychotic activity. Central dopamine receptors are subdivided into Dj, D2, and according to some sources, Dj receptors. These receptors have a high affinity for dopamine, but they differ in sensitivity to neuroleptics of various chemical classes. For example, drugs of the phenothiazine series are nonselective competitive Dj and D2 antagonists. Unlike phenoth-iazines, antipsychotics of the butyrophenone series such as haloperidol display selective action only on D2 receptors. 

Thioridazine has greater alpha adrenoceptor-blocking actions Haloperidol activates GABAergic neurons in the striatum Thioridazine has greater blocking actions on brain muscarinic receptors Haloperidol acts presynaptically to block dopamine release Which one of the following statements concerning the treatment of bipolar affective disorder is accurate ... 

Parkinsonian adverse effects occur more commonly with haloperidol than with thioridazine. One possible explanation is that thioridazine exerts more pronounced blocking actions at brain muscarinic receptors. This action partly compensates for dopamine receptor blockade in the ni-grostriatal tract, so that extrapyramidal function is more effectively maintained. A second possibility (not listed) is that haloperidol has a higher affinity for dopamine D2 receptors than does thioridazine. The answer is (D). 

In view of the known cellular actions of DA, such as increased K+ efflux and reduced Ca + currents associated with Dj receptor activation in cell lines, inhibition would be the expected response to DA, especially as cyclic AMP, which is increased by Dj receptor activation also inhibits striatal neurons. In fact although many DA synaptic effects are blocked by Dj antagonists like haloperidol, the role of Di receptors should not be overlooked. 

A number of different compounds of the piperidine and piperazine series with p-fluorobuty-rophenone group substitutions at the nitrogen atom display significant neuroleptic activity (haloperidol, trifluperidol, droperidol, methorin). There is a considerable interest in butyrophenone derivatives as antipsychotic agents as well as in anesthesiology. They exhibit pharmacological effects and a mechanism of action very similar to that of phenothiazines and thioxanthenes in that they block dopaminergic receptors. However, they are more selective with respect to D2 receptors. 

After dopamine was identified as a neurotransmitter in 1959, it was shown that its effects on electrical activity in central synapses and on production of the second messenger cAMP by adenylyl cyclase could be blocked by antipsychotic drugs such as chlorpromazine, haloperidol, and thiothixene. This evidence led to the conclusion in the early 1960s that these drugs should be considered dopamine-receptor antagonists and was responsible for the dopamine hypothesis of schizophrenia described earlier in this chapter. The antipsychotic action is now thought to be produced (at least in part) by their ability to block dopamine in the mesolimbic and mesocortical systems. 

Multiple sites in the CNS are affected by LSD. The drug shows serotonin (5-HT) agonist activity at presynaptic receptors in the midbrain, binding to both 5-HT and 5-HT2 receptors. Activation of the sympathetic nervous system occurs, which causes pupillary dilation, increased blood pressure, piloerection, and increased body temperature. Taken orally, low doses of LSD can induce hallucinations with brilliant colors, and mood alteration occurs. Tolerance and physical dependence have occurred, but true dependence is rare. Adverse effects include hyperreflexia, nausea, and muscular weakness. Sometimes high doses produce long-lasting psychotic changes in susceptible individuals. Haloperidol (see p. 127) and other neuroleptics can block the hallucinatory action of LSD and quickly abort the syndrome. 

The classical antipsychotic (see p. 380) drugs block dopamine receptors and their antipsychotic activity relates closely to this action, which notably involves the Dj-receptor, the principal target in Parkinson s disease. It comes as no surprise, therefore, that these drugs can induce a state whose clinical features are very similar to those of idiopathic Parkinson s disease. The piperazine phenothiazines, e.g. trifluoperazine, and the butyrophenones, e.g. haloperidol, are most commonly involved. In one series of 95 new cases of parkinsonism referred to a department of geriatric medicine, 51% were associated with prescribed drugs and half of these required hospital admission. After withdrawal of the offending drug most cases resolved completely in 7 weeks. But... 

Haloperidol blocks dopamine receptors in the brain and hence produces a very high incidence of movement disorders such as parkinsonism (see phenothiazine derivatives). Its mechanism of action in Gilles de la Tourette s syndrome is unknown. In addition to blocking dopamine receptors, haloperidol has many other central and peripheral effects it has weak peripheral anticholinergic and antiemetic... 

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