The effect of dopamine receptor antagonists on the motor function of the gastrointestinal tract. Dopamine receptor agonist Dopamine receptor agonist drugs
Moxonidine at a dose of 200 or 400 mcg orally, it reduces blood pressure through two mechanisms. It is an agonist at imidazoline I1 receptors in the rostroventrolateral medulla, thereby reducing the activity of the sympathetic nervous system. It is also believed that moxonidine has an agonistic effect on a2 receptors in the brain, producing an effect similar to that caused by clonidine.
However moxonidine is more selective for I1 receptors compared to α2 receptors, and lacks the respiratory suppressive effect attributed to central α2 activation. In this regard, moxonidine causes fewer side effects than clonidine. The decrease in blood pressure caused by moxonidine is usually accompanied by a decrease in heart rate that is shorter in duration and magnitude than the drop in blood pressure. The final T1/2 of moxonidine is 2 hours.
Elimination carried out mainly through the kidneys. Side effects are few and mild: dry mouth, dizziness and fatigue.
Dopamine D1 antagonists
Fenoldopan- a selective dopamine Dl agonist that causes vasodilation, increased renal perfusion and increased natriuresis in patients with hypertension. Phenoldopan has a short duration of action due to its short half-life of less than 10 minutes. It is used as parenteral therapy for surgical patients with high-risk hypertension, for perioperative management of patients undergoing kidney and other organ transplantation, and after the administration of radiocontrast agents to high-risk patients.
This is prototypical medicinal The drug is approved in the United States for use in hospital settings for the short-term treatment (up to 48 hours) of severe hypertension when it is necessary to obtain a rapid but easily reversible decrease in blood pressure, including malignant hypertension with deterioration of peripheral organ function. The short duration of action of fenoldopan avoids persistent excessive reductions in blood pressure in the emergency setting.
Effective The pharmacotherapeutic approach for hypertension is the use of a combination of two or more drugs. The combined use of drugs with different mechanisms of action makes it possible to reduce their doses, thereby reducing side effects. In the United States, there is a wide range of fixed-ratio combinations approved for use, some of which are available in finished form (tablets or capsules). The doses of drugs in combination are smaller, so side effects occur less frequently. In addition, it is easier for the patient to take all the necessary medications at once, rather than each one separately.
All combinations include the drugs discussed in this chapter except the loop diuretic pyretanide, which inhibits the Na+/K+/Cl- cotransporter.
Antagonists(3-adrenergic receptors and Ca2+ antagonists (dihydropyridines only), used in combination, are usually well tolerated by patients provided that the dose is carefully selected. The combination of nifedipine with β-adrenergic receptor antagonists can cause bradycardia and heart failure due to the synergism of drug effects (one of them is mediated by antagonism in in relation to b1-adrenergic receptors of the heart, the other – in relation to L-type Ca2+ channels of the ventricles).
Diuretic in combination with an ACE inhibitor (eg, hydrochlorothiazide and perindopril) is an effective combination for the treatment of hypertension that is well tolerated by many patients with mild to moderate hypertension. The advantage of combinations of diuretics with ACE inhibitors is their additive effect in lowering blood pressure. The combination of ACE inhibitors and Ca2+ antagonists is also effective in lowering blood pressure and is usually well tolerated. However, in this case, an additive effect, as a rule, does not occur.
This pharmacotherapeutic group combines drugs that have the ability to eliminate or alleviate the symptoms of Parkinson's disease (hereditary degenerative chronic progressive disease) and parkinsonism syndrome. The latter can be caused by various lesions of the central nervous system (infections, intoxication, trauma, atherosclerosis of cerebral vessels, etc.), as well as the use of certain drugs, incl. neuroleptics, calcium antagonists, etc.
The pathogenesis of Parkinson's disease and its syndromic forms remains unclear. However, it has been established that these conditions are accompanied by degeneration of nigrostriatal dopaminergic neurons and/or a decrease in dopamine content in the striopallidal system. Dopamine deficiency leads to increased activity of cholinergic interneurons and, as a consequence, the development of an imbalance of neurotransmitter systems. An imbalance between dopaminergic and cholinergic neurotransmission is manifested by hypokinesia (stiffness of movements), rigidity (pronounced hypertonicity of skeletal muscles) and resting tremor (constant involuntary trembling of the fingers, hands, head, etc.). In addition, patients develop postural disorders, increased salivation, sweating and secretion of the sebaceous glands, irritability and tearfulness.
The goal of pharmacotherapy for Parkinson's disease and its syndromic forms is to restore the balance between dopaminergic and cholinergic neurotransmission, namely: enhancing dopaminergic functions or suppressing cholinergic hyperactivity.
Drugs that can enhance dopaminergic transmission in the central nervous system include levodopa, dopamine receptor agonists, MAO type B and catechol-O-methyltransferase (COMT) inhibitors, etc.
Levodopa eliminates the deficiency of endogenous dopamine in the neurons of the striopallidal system. It is a physiological precursor of dopamine, which does not have the ability to penetrate the BBB. Levodopa penetrates the BBB via the amino acid mechanism, undergoes decarboxylation with the participation of DOPA decarboxylase and effectively increases the level of dopamine in the striatum. However, the process of decarboxylation of levodopa also occurs in peripheral tissues (where there is no need to increase dopamine levels), causing the development of undesirable effects such as tachycardia, arrhythmia, hypotension, vomiting, etc. Extracerebral production of dopamine is prevented by DOPA decarboxylase inhibitors (carbidopa, benserazide), which do not penetrate the BBB and do not affect the process of decarboxylation of levodopa in the central nervous system. Examples of combinations of levodopa + DOPA decarboxylase inhibitor are the drugs Madopar, Sinemet, etc. A significant increase in the level of dopamine in the central nervous system can lead to undesirable effects, such as the appearance of involuntary movements (dyskinesia) and mental disorders. The use of drugs with controlled release of the active substance (Madopar GSS, Sinemet SR) allows you to avoid pronounced fluctuations in the level of levodopa and a number of its side effects. Such drugs provide stabilization of plasma levels of levodopa, maintaining them at a higher level for several hours longer, as well as the possibility of reducing the frequency of administration.
It is possible to increase the content of dopamine in the striopallidal system not only by increasing its synthesis, but also by inhibiting catabolism. Thus, type B MAO destroys dopamine in the striatum. This isoenzyme is selectively blocked by selegiline, which is accompanied by inhibition of dopamine catabolism and stabilization of its level in the central nervous system. In addition, the antiparkinsonian effect of selegiline is due to neuroprotective mechanisms, incl. inhibition of the formation of free radicals. The degradation of levodopa and dopamine by methylation is blocked by inhibitors of another enzyme - COMT (entacapone, tolcapone).
Dopamine receptor agonists can also reverse signs of dopaminergic neurotransmission deficiency. Some of them (bromocriptine, lisuride, cabergoline, pergolide) are derivatives of ergot alkaloids, others are non-ergotamine substances (ropinirole, pramipexole). These drugs stimulate the D 1 , D 2 and D 3 subtypes of dopamine receptors and, compared to levodopa, are characterized by lower clinical efficacy.
Anticholinergics - m-cholinergic receptor antagonists (biperiden, benzatropine) can help restore the neurotransmitter balance in the central nervous system by suppressing cholinergic hyperactivity. Peripheral anticholinergic effects, along with impaired cognitive functions, significantly limit the use of this group of drugs. However, they are the drugs of choice for drug-induced parkinsonism.
Amantadine derivatives (hydrochloride, sulfate, glucuronide) interact with N-methyl-D-aspartate (NMDA) glutamate receptor ion channel receptors and reduce the release of acetylcholine from cholinergic neurons. A component of the antiparkinsonian effect of amantadine derivatives is also an indirect dopaminomimetic effect. They have the ability to increase the release of dopamine from presynaptic terminals, inhibit its reuptake and increase receptor sensitivity.
It has now become known that drugs based on reactive oxygen species (hydrogen peroxide) are capable of reflexively increasing the physiological effectiveness of neurotransmitters, regulating neurotransmitter interactions, and inducing antioxidant and neuroprotective mechanisms in the brain when administered nasally.
The therapeutic effect of antiparkinsonian drugs develops gradually. Some of them have a greater effect on hypokinesia and postural disorders (levodopa, dopamine receptor agonists), others weaken tremor and autonomic disorders (anticholinergics). It is possible to carry out both mono- and combined (drugs from different groups) antiparkinsonian therapy. It should be borne in mind that the treatment of Parkinson's disease and its syndromic forms is symptomatic, therefore the effects of antiparkinsonian drugs appear during the period of use and a short time after their discontinuation. The dosage of these agents should be individualized as much as possible. The prescription regimen provides for short-term breaks (1-2 per week) in administration to prevent the occurrence of tolerance. Long breaks in therapy with antiparkinsonian drugs are not recommended (severe or irreversible impairment of motor activity is possible), but if necessary, discontinuation of treatment is carried out gradually to avoid exacerbation of symptoms.
see also Intermediates: -Dopaminomimetics
Drugs
Drugs - 481 ; Trade names - 37 ; Active ingredients - 12
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Prokinetics- medications - stimulants of gastrointestinal motility.
Prokinetic group
In the domestic gastroenterological literature there is no single generally accepted list of prokinetics. Different gastroenterologists define the range of prokinetic drugs differently. Many of the prokinetics can also be included in other groups (antiemetics, antidiarrheals and even antibiotics). In the “theoretical” (scientific) plan of analysis of the group of prokinetics, it is important that only a minority of the prokinetics existing in the world are present on the Russian market. However, for practical medicine this does not matter. Prokinetics that are not registered in Russia today are either prohibited (for example, by the FDA in the USA) or do not have any advantages over the approved ones.
For the Russian patient, only two types of prokinetics are of interest: with the active substance domperidone(motilium, motilak, etc.) and with the active ingredient itopride(ganatone and itomed), as well as trimebutin, a myotropic antispasmodic, often classified as prokinetic (Alekseeva E.V. et al.). Previously common prokinetic agents (cerucal, raglan, etc.) are considered obsolete due to the large number of side effects. For the same reasons, bromopride (bimaral), which is similar in pharmaceutical properties to metoclopramide, has not been sold in the Russian Federation for several years (banned in the USA). Cisapride (Coordinax, etc.), which was previously considered promising, was banned in 2000 in both the USA and the Russian Federation. 
Other groups of drugs: 5-HT1 receptor agonists (buspirone, sumatriptan), which improve gastric accommodation after meals, motilin-like peptide ghrelin (ghrelin receptor agonist), gonadotropin-releasing hormone analogue leuprolide, kappa receptor agonists (fedotocin, azimadoline), which reduce visceral sensitivity, and others are at the stage of clinical study (Ivashkin V.T. et al.), the 5-HT 1 and 5-HT 4 agonist and the 5-HT 2 receptor antagonist cinitapride, which is registered in Spain, but not in Russia and the USA.
Promising and experimental prokinetics, but not yet registered in Russia, the USA and the European Union, include:
- antagonist of muscarinic M1 and M2 receptors, as well as acetylcholinesterase inhibitor acotiamide (Maev I.V. et al.)
- GABA B receptor agonists (eng. GABA B R) arbaclofen and lezogaberan (Sheptulin A.A.)
- antagonist of the metabotropic glutamate-5 receptor (mGluR 5) mavoglurant (Sheptulin A.A.)
- cholecystokinin receptor antagonist (CCK-A receptor) loxiglumide (Sheptulin A.A. et al., Titgat G.).
Trade names of prokinetic agents
Prokinetics - dopamine receptor antagonists
Dopamine receptor antagonists block D 2 -dopamine receptors and, thereby, have a stimulating motor function of the stomach and antiemetic effects. D2-dopamine receptor antagonists include: metoclopramide, bromopride, domperidone, dimethpramide. Itopride is also an antagonist of D2-dopamine receptors, but it is also an inhibitor of acelinecholine and, therefore, is often not considered in the group of dopamine receptor antagonists.
The widely known prokinetics cerucal and raglan (active substance metoclopramide), the less well-known bimaral (bromopride) belong to the first generation prokinetics. 
Domperidone is a second-generation prokinetic agent and, unlike metoclopramide (and bromopride), does not penetrate the blood-brain barrier and does not cause extrapyramidal disorders characteristic of metoclopramide: spasm of the facial muscles, trismus, rhythmic protrusion of the tongue, bulbar type of speech, spasm of extraocular muscles, spasmodic torticollis , opisthotonus, muscle hypertonicity, etc. Also, unlike metoclopramide, domperidone does not cause parkinsonism: hyperkinesis, muscle rigidity. When taking domperidone, side effects of metoclopramide such as drowsiness, fatigue, tiredness, weakness, headaches, increased anxiety, confusion, and tinnitus are less common and less pronounced. That's why Domperidone is a better prokinetic agent than metoclopramide
.
Prokinetics - dopamine receptor antagonists are used in the treatment of GERD, gastric and duodenal ulcers, functional dyspepsia, achalasia of the esophagus, diabetic gastroparesis, postoperative intestinal paresis, biliary dyskinesia and flatulence. 
Prokinetics from this group are also used for nausea and vomiting due to diet disorders, infectious diseases, early toxicosis of pregnancy, kidney and liver diseases, myocardial infarction, traumatic brain injury, anesthesia, radiation therapy, as a prophylaxis for vomiting before endoscopy and X-ray contrast studies. Dopamine receptor antagonists have no effect on vomiting for vestibular reasons. According to the pharmacological index, prokinetic dopamine receptor antagonists belong to the group “Gastrointestinal motility stimulants, including emetics.” For ATC - to group A03FA “Gastrointestinal motility stimulants”.
Neuroleptics - antagonists of dopamine D2 receptors with prokinetic properties
Some neuroleptics, in particular sulpiride and levosulpiride, have a prokinetic effect on the organs of the digestive system, therefore, when considering gastroenterological problems, they are classified as prokinetics, which have an antiemetic effect that activates the proximal intestine (Sablin O.A., Riezzo G. et al.) . Sulpiride has been widely used in gastroenterology for a long time due to its pronounced prokinetic activity, realized through a “regulating” effect on the central nervous system. Being a selective antagonist of dopamine receptors, it has moderate antipsychotic activity in combination with some stimulating and antidepressant effects (Maev I.V. et al.). According to the pharmacological index, sulpiride and levosulpiride belong to the group “Neuroleptics”, according to ATC - to the subgroup “N05AL Benzamides” of the group “N05A Antipsychotic drugs”. Acetylcholine agonists - stimulants of intestinal motility
Drugs in this group are most often only partially classified as prokinetics, although all of them have prokinetic properties. In Russia, the most famous of the drugs in this group is coordinax. However, its active substance, cisapride, being a cholinomimetic, can cause the development of long QT interval syndrome and, as a result, life-threatening heart rhythm disturbances. Therefore, although it has the best prokinetic properties among drugs in its group, cisapride is not currently recommended for use
and existing permissions for its use have been revoked. In a number of CIS countries, mosapride, which is similar in mechanism of action to cisapride, has been registered. Unlike cisapride, mosapride 
has little effect on potassium channel activity and therefore has a lower risk for cardiac arrhythmias. This group also includes: the domestically developed M-cholinomimetic aceclidine (approved for use in the USSR), reversible cholinesterase inhibitors (physiostigmine, distigmine bromide, galantamine, neostigmine monosulfate, pyridostigmine bromide), tegaserod and prucalopride.
Tegaserod and prucalopride, which are enterokinetics (prokinetics that selectively act on the intestines), were recently moved within the ATC from the section “A03 Drugs for the treatment of functional gastrointestinal disorders” to the section “A06 Laxatives”
Prokinetics - motilin receptor agonists
The hormone motilin is produced in the stomach and duodenum, increases the pressure of the lower esophageal sphincter and increases the amplitude of peristalsis in the antrum of the stomach, stimulating its emptying. Erythromycin (as well as other macrolides: azithromycin, clarithromycin, atilmotin) interact with motilin receptors, imitating the action of the physiological regulator of the gastroduodenal migratory motor complex. Erythromycin can cause powerful peristaltic contractions, similar to those of the migrating motor complex, accelerating gastric emptying of liquid and solid food, erythromycin increases the rate of gastric emptying in a number of pathological conditions, in particular gastroparesis in diabetics and patients with progressive systemic scleroderma, reduces intestinal transit time contents in the proximal colon. However, it has virtually no effect on esophageal motility and, therefore, is not used in the treatment of GERD (Maev I.V. et al.). However, erythromycin, when taken for a month or more, doubles the risk of mortality associated with impaired cardiac conduction and, therefore, is not considered as a promising prokinetic agent.
Professional medical articles addressing the use of prokinetics in the treatment of gastrointestinal diseases:.
On the website in the literature catalog there is a section “Prokinetics”, containing links to articles on the use of prokinetics in the treatment of diseases of the gastrointestinal tract.
Dopamine receptor agonists (bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, lisuride) are also used as primary treatment. Drugs in this group are specific central agonists of dopamine receptors. By mimicking the effects of dopamine, they produce the same pharmacological effects as levodopa.
Compared to levodopa, they are less likely to cause dyskinesia and other movement disorders, but more often have other side effects: edema, drowsiness, constipation, dizziness, hallucinations, nausea.
Inhibitors of monoamine oxidase type b (MAO-b) and catechol-o-methyltransferase (comt)
This group of drugs selectively inhibits the activity of enzymes that break down dopamine: MAO-B and COMT. Selegiline (MAO-B inhibitor), entacapone and tolcapone (COMT inhibitors) slow the steady progression of Parkinson's disease. Pharmacological effects are similar to levodopa, although their severity is much less severe. They allow you to enhance the effects of levodopa without increasing or even decreasing its total dose.
Indirect dopaminomimetics (amantadine, glutantan) increase the sensitivity of receptors to the corresponding mediator. These drugs enhance the release of dopamine from presynaptic terminals and inhibit its reverse neuronal uptake. Medicines in this group cause the same pharmacological effects as levodopa, that is, they predominantly suppress hypokinesia and muscle rigidity, with significantly less effect on tremor.
Central anticholinergic agents
Trihexyphenidyl is the main drug in the group of central anticholinergic drugs used to treat Parkinson's disease
Anticholinergic drugs are used to treat parkinsonism. The famous French doctor Jean Charcot used belladonna back in 1874 to reduce the increased salivation observed in the disease. They also noted a decrease in tremor when taking it. Subsequently, not only belladonna preparations were used for treatment, but also other anticholinergic drugs - atropine and scopolamine. After the advent of synthetic anticholinergic drugs, trihexyphenidyl (cyclodol), triperiden, biperiden, tropacin, etpenal, didepil and dynesin began to be used.
The use of anticholinergic drugs is pathogenetically justified. Damage to the substantia nigra and other nerve formations leads to significant changes in cholinergic and dopaminergic processes, namely an increase in cholinergic activity and a decrease in dopaminergic activity. Thus, central anticholinergic blockers “even out” neurotransmitter interactions.
Previously used belladonna preparations act predominantly on peripheral acetylcholine receptors and less on cholinergic receptors in the brain. In this regard, the therapeutic effect of these drugs is relatively small. At the same time, they cause a number of side effects: dry mouth, impaired accommodation, urinary retention, general weakness, dizziness, etc.
Modern synthetic antiparkinsonian central anticholinergic blockers are characterized by a more selective effect. They are widely used in the treatment of extrapyramidal diseases, as well as neurological complications caused by antipsychotics.
A distinctive property of central anticholinergics is that they have a greater effect on tremor; have a lesser effect on rigidity and bradykinesia. Due to the peripheral action, salivation decreases, and to a lesser extent, sweating and skin greasiness.
Drugs from the group of dopaminergic receptor agonists are represented by ergot alkaloid derivatives bromocriptine and cabergoline, the pyrimidine derivative piribedil and modern, more selectively acting drugs: pramipexole and ropinirole.
Mechanisms of action and pharmacological effects
One of the most promising areas of treatment for Parkinson's disease currently involves the use of dopamine receptor agonists. It has been established that postsynaptic dopamine receptors D1, D2, D3 are relatively preserved in Parkinson's disease and can directly respond to direct dopaminergic stimulation, which underlies the therapeutic effect of dopamine agonists. These drugs bypass degenerating neurons and do not increase dopamine circulation, which, according to some data, avoids the risk of worsening oxidative stress.
Prevention of oxidative stress is one component of the possible neuroprotective effects of dopamine receptor agonists.
As is known, dopamine agonists have a certain specificity for various receptors, which opens up prospects for optimizing their administration with a possible improvement in the tolerability of these drugs. Currently, five dopaminergic receptor subtypes have been studied. Subtypes D1 and D5 belong to the D1 receptor group, while D2, D3, D4 belong to the D2 receptor group. The main therapeutic target for Parkinson's disease is D2 receptors, which are widely distributed in the nigrostriatal, mesolimbic and mesocortical pathways. An important role in the formation of the “threshold” of dyskinesias belongs to D1 and D3.
In recent years, special attention has been paid to non-ergoline dopaminergic receptor agonists, including pramipexole, ropinirole, and piribedil. The effect of piribedil on all the main symptoms of Parkinson's disease (bradykinesia, tremor, rigidity), as well as a decrease in the severity of depression, has been demonstrated. The effect of piribedil as an α2-adrenergic receptor antagonist has also been established, which causes a positive effect on cognitive and motor impairment in Parkinson's disease.
Pramipexole binds to presynaptic D2 receptors and postsynaptic D2 and D3 receptors; Moreover, pramipexole is characterized by an affinity for D3 receptors. Activation of presynaptic D2 autoreceptors inhibits the synthesis and release of dopamine, as well as dopaminergic neuronal activity. According to research, pramipexole, being a full agonist of D2 receptors, in turn, has a pronounced dose-dependent suppressive effect on the activity of dopaminergic neurons in the striatum and mesolimbic region. In contrast to pramipexole, bromocriptine, pergolide and lisuride only partially suppress neuronal activity, apparently being partial agonists of D2 receptors.
Pharmacokinetics
Dopaminergic receptor agonists are well absorbed from the gastrointestinal tract (GIT), but have variable bioavailability. Excretion of dopaminergic receptor agonists occurs primarily through the kidneys and partly through the intestines.
Treatment with dopamine receptor agonists
Traditionally, dopamine receptor agonists are used as adjunctive therapy to improve the effect of levodopa, reduce the dose and correct fluctuations.
Other indications for which it is advisable to prescribe dopaminergic receptor agonists:
- prolactinomas, hyperprolactinemia and conditions requiring cessation of lactation - bromocriptine, cabergoline, pergolide, lisuride;
- acromegaly - bromocriptine, pergolide, lisuride.
In addition, piribedil is used for circulatory disorders of the eye.
Tolerability and side effects
A fairly rare but serious side effect has been observed in the form of pulmonary and retroperitoneal fibrosis and erythromelalgia. Pramipexole and ropinirole rarely cause sudden sleep attacks.
Contraindications
Main contraindications to the use of dopaminergic receptor agonists:
- hypersensitivity to ergot alkaloids (bromocriptine, cabergoline);
- psychosis, anxiety in old age, delirium (bromocriptine, cabergoline, lisuride);
- severe forms of cardiovascular diseases, uncontrolled arterial hypertension (bromocriptine, piribedil);
- pregnancy and lactation (bromocriptine, cabergoline, pramipexole);
Interaction
A decrease in the effect of most dopaminergic receptor agonists (bromocriptine, cabergoline, pergolide, piribedil, pramipexole) is characteristic when administered simultaneously with dopamine receptor blockers: antipsychotics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide.
The simultaneous use of dopaminergic receptor agonists and macrolide antibiotics, including erythromycin, is also not recommended, since the bioavailability of the drugs and the severity of their side effects may increase.
Ethanol may increase the side effects of bromocriptine.
The article was prepared and edited by: surgeon
