Dopamine antagonist

Template:Short description Template:Distinguish Template:Infobox drug class

A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and have been used in treating schizophrenia, bipolar disorder, and stimulant psychosis.<ref name="Beaulieu_20116">Template:Cite journal</ref> Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.

Receptor pharmacology

File:Dopamine Receptor Flowchart.png

Dopamine receptor flow chart

Dopamine receptors are all G protein–coupled receptors, and are divided into two classes based on which G-protein they are coupled to.<ref name="Beaulieu_20116"/> The D₁-like class of dopamine receptors is coupled to Gα_s/olf and stimulates adenylate cyclase production, whereas the D₂-like class is coupled to Gα_i/o and thus inhibits adenylate cyclase production.<ref name="Beaulieu_20116"/>

D₁-like receptors: D₁ and D₅

D₁-like receptors – D₁ and D₅ are always found post-synaptically. The genes coding these receptors lack introns, so there are no splice variants.

D₁ receptors

D₁ receptors are found mainly on neurons in the nucleus accumbens<ref name="Sokoloff_20065">Template:Cite journal</ref> as well as substantia nigra,<ref name="Beaulieu_20116"/> striatum,<ref name="Beaulieu_20116"/> amygdala,<ref name="Beaulieu_20116"/> frontal cortex<ref name="Beaulieu_20116"/> and olfactory bulb and retina<ref name="Beaulieu_20116"/>
Also found (in lower levels) in the hypothalamus, thalamus, cerebellum and hippocampus<ref name="Beaulieu_20116"/>
Peripherally, these receptors have been found in the renal artery, mesenteric artery, and splenic artery where activation leads to vasodilation.<ref name="Missale_19985">Template:Cite journal</ref> In addition, D₁ receptors have been found in the kidney<ref name="Missale_19985"/>

D₅ receptors

Low levels of D₅ receptors have been found in the hypothalamus, prefrontal cortex and cingulate cortex; as well as memory areas such as hippocampus, dentate gyrus and entorhinal cortex.<ref name="Beaulieu_20116"/>
In addition, D₅ receptors have been found in the kidney<ref name="Missale_19985"/>

D₂-like receptors: D₂, D₃ and D₄

D₂-like receptors – unlike the D₁-like class, these receptors are found pre and post-synaptically. The genes that code these receptors have introns, leading to many alternately spliced variants.

D₂ receptors

D₂ receptors are found in the striatum, substantia nigra, ventral tegmental area, hypothalamus, cortex, septum, amygdala, hippocampus, and olfactory tubercle.<ref name="Beaulieu_20116"/>
These receptors have also been found in the retina and pituitary gland.<ref name="Beaulieu_20116"/>
Peripherally, these receptors have been found in the renal, mesenteric, and splenic arteries as well as on the adrenal cortex and medulla and within the kidney.<ref name="Missale_19985"/>

D₃ receptors

D₃ receptors are highly expressed on neurons in islands of Calleja and nucleus accumbens shell and lowly expressed in areas such as the substantia nigra pars compacta, hippocampus, septal area, and ventral tegmental area.<ref name="Beaulieu_20116"/><ref name="Sokoloff_20065"/>
Additional studies have found these receptors peripherally in the kidney<ref name="Missale_19985"/>

D₄ receptors

D₄ receptors are found in amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticula, the thalamus, the retina and the kidney<ref name="Beaulieu_20116"/><ref name="Missale_19985"/>

Implications in disease

The dopaminergic system has been implicated in a variety of disorders. Parkinson's disease results from loss of dopaminergic neurons in the striatum.<ref name="Beaulieu_20116"/> Dopamine is believed to play a significant role in the pathogenesis of schizophrenia, with most effective antipsychotics blocking D₂ receptors.<ref name="Beaulieu_20116"/><ref>Template:Cite journal</ref><ref name="Missale_19985"/> Additional studies hypothesize dopamine dysregulation is involved in Huntington's disease, ADHD, Tourette's syndrome, major depression, manic depression, addiction, hypertension and kidney dysfunction.<ref name="Beaulieu_20116"/><ref name="Missale_19985"/><ref>Template:Cite journal</ref>

Dopamine receptor antagonists are used in the management of a broad range of diseases and conditions such as schizophrenia, bipolar disorder, nausea and vomiting.<ref name="Beaulieu_20116" />

Melatonin suppresses dopamine activity<ref>Template:Cite journal</ref> as part of normal circadian rhythm functions, and pathological imbalances have been implicated in Parkinson's disease<ref>Template:Cite journal</ref>

Side effects

They may include one or more of the following and last indefinitely even after cessation of the dopamine antagonist, especially after long-term or high-dosage use:

Cardiovascular disease<ref name="Young_2015">Template:Cite journal</ref><ref name="Arana_2000">Template:Cite journal</ref>
File:EPS Flowchart.png
Extrapyramidal symptoms (EPS) associated with typical antipsychotics:
- Early stage – occurs at onset of treatment or following increased dose, patients recover when dose is decreased<ref name="Divac_2014">Template:Cite journal</ref>
  - Acute dystonias<ref name="Divac_2014" /> – muscle spasms and sustained abnormal postures and onset occurs within a few days; can be treated with anticholinergics
    - risk factors include age, gender and family history<ref name="Divac_2014" />
  - Akathisia<ref name="Divac_2014" /><ref name="Missale_19985"/> - pacing and restlessness and onset occurs within the first few months; can be treated with beta blockers and benzodiazepines
  - Parkinsonism due to effects on the nigrostriatal pathway<ref name="Divac_2014" /><ref name="Missale_19985"/> - includes tremors, bradykinesia and muscle rigidity
    - risk factors include age and gender<ref name="Divac_2014" />
- Late stage – occurs after prolonged (months-years) treatment, symptoms persist even after dose is decreased<ref name="Divac_2014" />
  - Tardive dyskinesia<ref name="Divac_2014" /><ref name="Missale_19985"/> - includes involuntary and repetitive facial movements
    - risk factors include age, race and gender<ref name="Divac_2014" />
- It is hypothesized that these effects are due to chronic blockade of the D₂ receptor<ref name="Missale_19985"/>
Hyperprolactinaemia due to blockade of the D₂ receptors in the anterior pituitary leading to increased prolactin release<ref name="Young_2015" /><ref name="Nadal_20014">Template:Cite journal</ref>
Increased appetite including increased craving and binge eating that lead to weight gain<ref name="Young_2015" /><ref name="Deng2013">Template:Cite journal</ref><ref name="Mortimer_20045">Template:Cite journal</ref>
Increased risk for insulin resistance<ref name="Deng2013" />
Sexual dysfunction<ref name="Young_2015" /><ref name="Arana_2000" />
Metabolic changes with increased risk of obesity and diabetes mellitus type 2<ref name="Young_2015" /><ref name="Deng2013" />
Sedation<ref name="Young_2015" /><ref name="Arana_2000" />
Neuroleptic Malignant Syndrome<ref name=":2">Template:Cite journal</ref> is a medical emergency caused by a decrease in dopaminergic activity, resulting in a central D₂ receptor blockade.<ref name=":2" />

Examples

First-generation antipsychotics (typical)

First generation antipsychotics are used to treat schizophrenia and are often accompanied by extrapyramidal side effects.<ref name="Beaulieu_20116"/> They inhibit dopaminergic neurotransmission in the brain by blocking about 72% of the D2 dopamine receptors.<ref name=":0">Template:Cite journal</ref> They can also block noradrenergic, cholinergic, and histaminergic activity.<ref name=":0" />

Benperidol<ref name="Beaulieu_20116"/> binds D₂ and some serotonin receptors.<ref name="Leucht_2005">Template:Cite journal</ref> It is absorbed very easily and has a high first pass effect.<ref name="Leucht_2005" />
Chlorpromazine binds D₃ with the highest affinity, but also binds D₁, D₂, D₄ and D₅<ref name="Sokoloff_20065"/><ref name="Missale_19985"/>

File:Chlorpromazine.svg

Chemical Structure of typical antipsychotic chlorpromazine

Clopenthixol<ref name="Beaulieu_20116"/>
Droperidol is used as an antipsychotic and antiemetic.<ref name="Beaulieu_20116"/>
Haloperidol binds D₂, D₃ and D₄ with the highest affinity, but also binds D₁ and D_5.<ref name="Beaulieu_20116"/><ref name="Sokoloff_20065"/><ref name="Missale_19985"/> Haloperidol also has a risk for QTc prolongation.<ref name=":1" />
Fluphenazine binds D₂ and D₃ with the highest affinity but D₁ and D₅ as well<ref name="Beaulieu_20116"/><ref name="Sokoloff_20065"/>
Flupentixol binds D₁, D₂, D₃, and D₅<ref name="Sokoloff_20065"/> and is also used as an antidepressant.<ref name="Beaulieu_20116"/>
Fluspirilene<ref name="Beaulieu_20116"/>
Penfluridol<ref name="Beaulieu_20116"/>
Perazine<ref name="Beaulieu_20116"/>
Perphenazine<ref name="Beaulieu_20116"/>
Pimozide binds D₂ and D₃ with high affinity, also binds D₄ receptors<ref name="Beaulieu_20116"/><ref name="Sokoloff_20065"/>
Spiperone binds D₂, D₃ and D₄ with high affinity; can also bind D₁<ref name="Beaulieu_20116"/><ref name="Sokoloff_20065"/>
Sulpiride binds D₂ and D₃<ref name="Beaulieu_20116"/><ref name="Sokoloff_20065"/> and is also used as an antidepressant.<ref name="Beaulieu_20116"/>
Thioridazine binds D₂, D₃ and D₄ with high affinity; can also bind D₁ and D₅ at higher concentrations<ref name="Sokoloff_20065"/> Thioridazine has the highest associated risk of QTc prolongation among neuroleptics.<ref name=":1" />

Second-generation antipsychotics (atypical)

These drugs are not only dopamine antagonists at the receptor specified, but also act on serotonin receptor 5HT_2A.<ref name=":0" /><ref name="Beaulieu_20116"/> These drugs have fewer extrapyramidal side effects and are less likely to affect prolactin levels when compared to typical antipsychotics.<ref name="Nadal_20014"/>

Amisulpride binds D₂ and D₃<ref name="Sokoloff_20065"/> and is used as an antipsychotic, antidepressant and also treats bipolar disorder.<ref name="Beaulieu_20116"/> It treats both the positive and negative symptoms of schizophrenia.<ref name="Mortimer_20045"/>
Asenapine binds D₂, D₃ and D₄<ref>Template:Cite journal</ref> and is used to treat bipolar disorder and schizophrenia.<ref>Template:Cite journal</ref> Its side effects include weight gain but there is lower risk for orthostatic hypotension and hyperprolactinemia.
Aripiprazole binds D₂ as a partial agonist but antagonizes D_3.<ref name="Yang_2015">Template:Cite journal</ref> In addition, aripiprazole treats schizophrenia, bipolar disorder (mania),<ref>Template:Cite journal</ref> depression,<ref name="Beaulieu_20116"/> and tic disorders<ref name="Yang_2015" />

File:Clozapine.png

Clozapine

Clozapine binds D₁ and D₄ with the highest affinity but still binds D₂ and D₃.<ref name="Sokoloff_20065"/> Clozapine is usually only prescribed when treatment with other antipsychotics has failed, due to its rare but potentially very serious side effects.<ref name="Mortimer_20045"/> It also requires regular white blood cell counts, initially weekly then less frequently, to monitor for potential neutropenia, at least for the first 1-2 years of treatment.<ref name="Mortimer_20045"/><ref>Template:Cite journal</ref>
Loxapine binds D₂, D₃ and D₄ with high affinity; can also bind D_1.<ref>Template:Cite journal</ref> Loxapine is often used to treat agitated and violent patients with neuropsychiatric disorders such as bipolar disorder and schizophrenia.<ref>Template:Cite journal</ref>
Nemonapride binds D₃, D₄ and D_5.<ref name="Missale_19985"/>
Olanzapine binds all receptors<ref name="Sokoloff_20065"/> and is used to treat the positive and negative symptoms of schizophrenia as well as bipolar disorder and depression.<ref name="Beaulieu_20116"/> It has been associated with significant weight gain.<ref name="Mortimer_20045"/>
Quetiapine binds D₁, D₂ and D₃ and can bind D₄ at high concentrations.<ref name="Sokoloff_20065"/> It is used to treat the positive symptoms of schizophrenia,<ref name="Mortimer_20045" /> bipolar disorder and depression.<ref name="Beaulieu_20116"/> Of the second generation antipsychotics, quetiapine may produce fewer parkinsonian side effects.<ref>Template:Cite journal</ref>
Paliperidone binds D₂, D₃ and D₄ with high affinity; can also bind D₁ and D₅.<ref name="Corena-McLeod_20152">Template:Cite journal</ref>
Remoxipride binds D₂ receptors with relatively low affinity.<ref name="Sokoloff_20065"/><ref name="Nadal_20014"/><ref name="Beaulieu_20116"/>
Risperidone binds D₂, D₃ and D₄ receptors.<ref name="Beaulieu_20116"/><ref name="Sokoloff_20065"/><ref name="Corena-McLeod_20152" /> Risperidone not only treats the positive and negative symptoms of schizophrenia<ref name="Mortimer_20045" /> but also treats bipolar disorder.<ref name="Beaulieu_20116"/>
Tiapride blocks D₂ and D₃ and is used as an antipsychotic.<ref name="Beaulieu_20116"/> It is also often used to treat dyskinesias, psychomotor agitations, tics, Huntington's chorea and alcohol dependence.<ref>Template:Cite journal</ref>
Ziprasidone blocks the D₂ receptor<ref>Template:Cite journal</ref> and is used to treat schizophrenia, depression and bipolar disorder.<ref name="Beaulieu_20116"/> There is controversy on whether Ziprasidone treats negative symptoms and it has well documented gastrointestinal side effects.<ref name="Mortimer_20045" /> Ziprasidone can also cause QTc prolongation.<ref name=":1">Template:Cite journal</ref>