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Dopamine receptor antagonists

As peripheral and central dopaminergic receptors are rather similar, the specificity of action of an antagonist on peripheral or central receptors depends primarily on its pharmacokinetic features. If the drug does not cross (or little) the blood-brain barrier, the peripheral effects will prevail and conversely in the case of good penetration in the brain.

Peripheral dopaminergic antagonists

Dopamine has an emetic effect and inhibitis digestive motricity; its antagonists have antiemetic and digestive motility stimulant effects. Dopaminergic receptors in the chemoreceptor trigger zone responsible for vomiting are accessible to dopaminergic antagonists which do not cross the blood-brain barrier. Drugs stimulanting gastrointestinal motility are called prokinetic agents and are used specially in treating gastroesophageal reflux.

The two principal peripheral antagonists of dopamine are domperidone and metoclopramide.

  • Domperidone
    Domperidone, chemically derived from butyrophenones, has a poor penetration into the brain and it does not induce, under usual conditions of use, central adverse effects resulting from blocking of central dopaminergic receptors.
    Domperidone is used in the preventive and curative treatment of nausea and vomiting and dyspepsia with motility disorder. It reinforces oesophago-gastroduodenal motility, without modifying digestive secretions.
    It is also used to reduce the peripheral effects of dopaminergic drugs such as L-DOPA.

    Effects and therapeutic uses of metoclopramide, a derivative of benzamides, are the same as those of domperidone but metoclopramide crosses the blood-brain barrier more easily than domperidone and has more frequently central adverse effects similar to those of neuroleptics, in particular acute dyskinesia, especially in the child.
    Metoclopramide also activates serotonin receptors; it has 5HT4 agonist properties partially responsible for increase of intestinal motility.

    Metoclopramide

    METOCLOPRAMIDE, Oral solution

  • Metopimazine and alizapride
    The chemical structure of metopimazine is related to that of phenothiazines and that of alizapride to benzamides. Both have neuroleptic properties and are used as antiemetic agents

Central dopaminergic antagonists: neuroleptics, antipsychotics

The term neuroleptics indicates dopamine receptors antagonists active in the treatment of psychoses.

The central effects of neuroleptics prevail over their peripheral effects which exist however. The therapeutic use of neuroleptics, whatever their chemical structure and their other parallel properties, is the treatment of psychoses.

Psychoses, schizophrenia in particular, are very complex diseases involving negative symptoms (poverty of speech and expression, indifference, carelessness…) and productive symptoms (hallucinations, delusion, unsuited behavior, , aggressiveness). Neuroleptics, also called antipsychotics, improve most of these symptoms, especially the productive ones.

Receptors implicated in neuroleptic action

All neuroleptics inhibit dopaminergic receptors and there is a good correlation between their antidopaminergic activity, in particular of D2 type, and their clinical efficacy. But many differences can exist between available neuroleptics.

  1. N euroleptics have particular affinities for each subclass of dopaminergic receptors and there are several types of dopaminergic receptors D1, D2, D3, D4 and D5. These receptors have presynaptical and postsynaptical distribution and selective localization in different areas of the brain.
  2. Many neuroleptics have, in addition to their antidopaminergic effect, other pharmacological properties, from which result beneficial and adverse effects:
    • 5HT2 antagonist effect which contributes to the antipsychotic effect.
    • alpha-1 adrenolytic effect, partially responsible for sedation and postural hypotension
    • anticholinergic effect, responsible for several adverse effects: mouth dryness, constipation, urinary disturbances, etc
    • H1 antihistamine effect which induces sedation

Effects

In animal experiments, neuroleptic agents elicit:

  • sedation, reduced motility
  • in high doses, catalepsy, i.e. maintenance of unusual positions given to animals by the experimenter
  • inhibition of conditioned reflexes with maintenance of primary reflexes
  • inhibition of agitation, stereotypies, and vomiting induced by apomorphine or amphetamine.

In human beings, the effects of neuroleptics are different in healthy subjects and patients with psychosis:

  1. In healthy subjects, to which they should not be administered, they elicit drowsiness, indifference, and several adverse effects of the same type as those which are described further.
  2. In psychotic patients, they have three principal effects:
    • sedative effect which results in drowsiness, diminution of vigilance, agitation and excitement
    • antideliriant and antihallucinogenic effects: decrease of delusion and hallucinations
    • anti-autistic effect: patients become more communicative and have a better contact with reality.

Classification

Neuroleptics can be classified according to various criteria, chemical structure, clinical properties:, conventional or atypical, duration of action, formulation.

  1. According to their chemical structure:
    The chemical classification distinguishes three principal groups: phenothiazines, butyrophenones and benzamides.

    The first neuroleptic agent, chlorpromazine, a phenothiazine, was discovered in France in 1952. H aloperidol, the first butyrophenone agent, was discovered in Belgium in 1958, and the first benzamide, sulpiride, discovered in France in 1965.
  2. According to clinical features: importance of sedative effect, of extrapyramidal side effects, of efficacy in psychoses resistant to other drugs. For example levomepromazine and sultopride are s edative neuroleptics, given in psychoses where agitation prevails. Droperidol, which was largely used as a sedative neuroleptic has been withdrawn from the market in many countries because of the risk of heart rhythm disorder. Clozapine is recognized to be able to improve psychoses resistant to other neuroleptics.
  3. According to receptor affinities. There are a lot of tables in literature giving the affinities (dissociation constants) of neuroleptics for classes and subclasses of receptors. All neuroleptics known until now have high affinity for dopaminergic receptors which they inhibit. Some neuroleptics have also a high affinity for 5-HT2 receptors which they inhibit. Generally, atypical neuroleptics have a 5-HT2 antagonist effect.
  4. Typical (conventional) and a typical neuroleptics: the name atypical neuroleptics was given to some neuroleptics such as clozapine, risperidone and olanzapine ( See “Serotonin, serotoninomimetics, antagonists”. ) because they improve psychotic patients not improved by other neuroleptics or give little extrapyramidal adverse effects.
    • Clozapine, known since 1965, inhibits preferentially D4 dopaminergic receptors with little extrapyramidal disorders and little effect on prolactin secretion. It has a 5HT2 serotonergic antagonist effect. and antimuscarinic and alpha-1adrenolytic effects. Its adrenolytic effect could explain its sedative action. It improves patients with psychosis resistant to other neuroleptics. It is also used to reduce psychotic symptoms such as hallucinations, delusion appearing in parkinsonian patients treated by dopaminomimetic drugs. Its major disadvantage is to cause agranulocytosis in 0,5 to 1% of treated patients
    • Olanzapine, loxapine and risperidone are more recent antipsychotics whose properties are quite similar to those of the clozapine, without inducing frequent agranulocytosis as does clozapine ( See “Serotonin, serotoninomimetics, antagonists”).
    • Sulpiride and amisulpride are sometimes classified as atypical neuroleptics although they have no serotonergic effect. They inhibit preferentially D2 and D3 receptors of limbic localization.
    • Aripiprazole is a new neuroleptic antagonist of postsynaptic D2 dopaminergic receptors and agonist of presynaptic receptors (autoreceptors) whose stimulation inhibits dopamine release. Aripiprazole has, in addition, a 5-HT2A antagonist effect and a 5-HT1A agonist effect.
  5. According to duration of action:
    Psychotic disorders require an uninterrupted treatment for a long duration. In certain patients, long-acting neuroleptic formulations are used. They are generally administered by intramuscular injection once or twice per month. In fact, they are composed of the same active molecules as those used by oral route but specially prepared, generally by esterification, to obtain compounds which gradually release the active product from the injection place during a few weeks.

Among long-acting neuroleptics, penfluridol is administered by oral route, once per week, because it has a slow and sustained digestive absorption and a long elimination half-life ,.

On the whole, the same neuroleptic can be put in several groups according to the selected criterion. There is no absolute criterion to differentiate” typical” and “atypical” neuroleptics. To restrain the term antipsychotics to only atypical neuroleptic agents is unjustified.  

Pharmacokinetics

The pharmacokinetics of neuroleptic agents present some characteristics.

  • Variable bioavailability:
    For a given dose of a neuroleptic agent, the plasma concentration varies from individual to individual in important proportions, the difference varying from 1 to 20.
  • Many metabolites:
    Most neuroleptics have many metabolites, sometimes active. In principle, for drug monitoring, it would be necessary to measure the plasma levels of all active products. The plasma half-life of the active products is generally long, explaining that once daily intake is enough and that the effect of the treatment, even with a non depot preparation, does not disappear immediately after its discontinuation, but attenuates gradually over days or weeks.
  • Efficacy versus blood levels:
    For a given plasma concentration (of active product), there is not an identical therapeutic effect in different patients.

Therapeutic uses

Therapeutic indications of neuroleptics are psychoses and they are called antipsychotics. They reduce manic states (excitation, aggressiveness, insomnia), delirious states (delusion, hallucinations) and to a lesser degree the severity of the negative symptoms of the psychosis. They do not cure the psychotic patient but attenuate considerably the symptoms of his disease.

Neuroleptics are also used in the treatment of the Gilles de la Tourette syndrome (tics).

Although all the neuroleptic agents have common features, more sedative products are used for acutely agitated patients and incisive products when autism prevails. Atypical neuroleptics ( See “Serotonin, serotoninomimetics, antagonists”. ) are more and more used, even if their superiority over typical neuroleptics prescribed in a good dosage, is not always obvious.

Whatever the neuroleptic, for a long course treatment, the lowest dose giving an acceptable improvement of the patient must be prescribed.

Available preparations

  • Phenothiazines
    Chlorpromazine, levomepromazine, cyamepromazine, thioridazine, propericiazine,fluphenazine, pipotiazine, perphenazine and related compounds zuclopenthixol, flupentixol
  • Butyrophenones
    Haloperidol, Penfluridol, Pipamperone, and a related compound pimozide 

    Haloperidol

    Haloperidol Tablets

    HALDOL DECANOATE Injection

    Pimozide

    ORAP* Tablets

  • Benzamides
    Sulpiride, Amisulpride, Tiapride, Sultopride
  • Atypical neuroleptics
    Loxapine, carpipramine, clozapine, olanzapine, risperidone
  • Long-action neuroleptics
    • By intramuscular injection ( sustained release formulations)
      Haloperido, Flupentixol, Zuclopentixol, Pipotiazine, Fluphenazine, Perphenazine
    • By oral route
      Penfluridol

Taking into account the multiple available formulations of each neuroleptic, the quantity of active product varying from 1 to 20 per unit, the doctor who renews a prescription must ensure that the same formulation is used by the patient to avoid a change of dose.

Adverse effects

Neuroleptic agents have many adverse effects. This should not prevent their prescription when it is necessary to control a psychotic state but it is necessary to use the minimal effective dose.

  1. Neurological
    • Sedation, drowsiness.
    • Acute dyskinesia occurs in first hours or first days after the initiation of the treatment by a neuroleptic. Acute dyskinesia is characterized by intermittent muscular spasms, affecting especially face and neck: torticollis, trismus, tongue protrusion, oculogyric attack, opistothonos. These symptoms, linked to inhibition of D2 dopaminergic receptors of the striatum, are distressing but may be controlled by anticholinergic antiparkinsonian drugs such as trihexyphenidyl The frequency of acute dyskinesias is lower with atypical neuroleptics like clozapine, olanzapine, risperidone that with conventional neuroleptics.
    • Tardive dyskinesia, or lingual-facial-buccal dyskinesia, occurs after a long treatment with high doses of neuroleptics,. These abnormal movements persist a long time after the discontinuation of neuroleptic agents, discontinuation which can worsen them. They are not improved by anticholinergic drugs such as trihexyphenidyl.
    • Pseudo-parkinsonism with akinesia ( slowness of movements), rest and postural tremor, rigidity, hypertonicity. The incidence of these effects is less frequent with atypical neuroleptics.
    • Akathisia or impossibility of remaining motionless.
    • Rare but severe hyperthermia accompanied by muscular rigidity, called neuroleptic malignant syndrome whose mechanisms are complex .
    • Decrease of seizure threshold, for example with clozapine.
    • Confusional syndrome: the antimuscarinic effect of most of neuroleptics contributes to appearance of confusional states.
    • Passivity and perhaps a certain depressive state.
  2. Digestive
    • Mouth dryness
    • Hypersalivation, with clozapine for example
    • Constipation, linked often to antimuscarinic effect.
  3. Cardiovascular
    • Postural hypotension
    • Electrocardiographic disorders. A lengthening of QT space was observed during the use of neuroleptics such as droperidol which now is not available in many countries and sultopride by injectable route in the treatment of agitation
    • possible implication of neuroleptics in sudden deaths has been evoked.
  4. Endocrine
    • Hyperprolactinemia at the origin of galactorrhea, gynecomastia, amenorrhea, decreased libido, erection and ejaculation disorders
    • weight gain, in particular with atypical neuroleptics such as olanzapine.
    Neuroleptics such as clozapine and olanzapine have been suspected to increase the risk of diabetes.
  5. Allergic reactions
    • Photosensitization
    • Blood disorders: thrombopenia, agranulocytosis particulaly with clozapine.
  6. Tératogenesis
    The old neuroleptic agents such as chlorpromazine are not teratogenic.

In spite of this long list of adverse effects, neuroleptics are the only effective drugs for the treatment of psychotic disorders and it is preferable to prescribe them at the beginning of the disease than after a long course without treatment.

The neuroleptic agents do not induce psychic addiction, whichis easily conceivable since dopaminergic stimulation is involved in reward and addiction..


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Quizz : Q 23
Hyperprolactinemia is an adverse effect frequently observed during treatment with:
ACE inhibiters
anxiolytic benzodiazepines
hypnotic benzodiazepines
neuroleptic agents
beta-blockers

... more quizz
25 Acute dyskinesia occurring a short time a...
35 Clozapine (Leponex*) is:
36 Adverse effects of neuroleptic agents, su...
37 The following drug (s) decrease(s) or sup...
50 The following drug (s) induce(s) adversel...
115 The following neuroleptic(s) is (are) che...
135 The following drugs are classified among...
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