Dopamine

As a biogenic amine, dopamine belongs to a group of substances produced in the organism by decarboxylation of amino acids. Besides dopamine and norepinephrine formed from it, this group includes many other messenger molecules such as histamine, serotonin, and γ-aminobutyric acid.

Dopamine actions and pharmacological implications (A). In the CNS, dopamine serves as a neuromediator. Dopamine receptors are also present in the periphery. Neuronally released dopamine can interact with various receptor subtypes, all of which are coupled to G-proteins. Two groupings can be distinguished: the family of D1-like receptors (comprising subtypes D1 and D5) and the family of D2-like receptors (comprising subtypes D2, D3, and D4). The subtypes differ in their signal transduction pathways. Thus, synthesis of cAMP is stimulated by D1-like receptors but inhibited by D2-like receptors.

Released dopamine can be reutilized by neuronal reuptake and re-storage in vesicles or can be catabolized like other endogenous catecholamines by the enzymes MAO and COMT (p.86).

Various drugs are employed therapeutically to influence dopaminergic signal transmission.

Antiparkinsonian agents. In Parkinson disease, nigrostriatal dopamine neurons degenerate. To compensate for the lack of dopamine, use is made of L-dopa as the dopamine precursor and of D2 receptor agonists (cf. p.188).

Prolactin inhibitors. Dopamine released from hypothalamic neurosecretory nerve cells inhibits the secretion of prolactin from the adenohypophysis (p.238). Prolactin promotes production of breast milk during the lactation period; moreover it inhibits the secretion of gonadorelin. D2 receptor agonists prevent prolactin secretion and can be used for weaning and the treatment of fe-

male infertility resulting from hyperprolactinemia.

The D2 agonists differ in their duration of action and, hence, their dosing interval; e.g., bromocriptine 3 times daily, quinagolide once daily, and cabergoline once to twice weekly.

Antiemetics. Stimulation of dopamine receptors in the area postrema can elicit vomiting. D2 receptor antagonists such as metoclopramide and domperidone are used as antiemetics (p.342). In addition they promote gastric emptying.

Neuroleptics. Various CNS-permeant drugs that exert a therapeutic action in schizophrenia display antagonist properties at D2 receptors; e.g., the phenothiazines and butyrophenone neuroleptics (p.232).

Dopamine as a therapeutic agent (B). When given by infusion, dopamine causes a dilation of renal and splanchnic arteries that results from stimulation of D1 receptors.This lowers cardiac afterload and augments renal blood flow, effects that are exploited in the treatment of cardiogenic shock. Because of the close structural relationship between dopamine and norepinephrine, it is easy to understand why, at progressively higher doses, dopamine is capable of activating β1- adrenoceptors and finally α1-receptors. In particular, α-mediated vasoconstriction would be therapeutically undesirable (symbolized by red warning sign).

Apomorphine is a dopamine agonist with a variegated pattern of usage. Given parenterally as an emetic agent to aid elimination of orally ingested poisons, it is not without hazards (hypotension, respiratory depression). In akinetic motor disturbances, it is a back-up drug. Taken orally, it supposedly is beneficial in erectile dysfunction.

Histamine Effects and Their Pharmacological Properties

Functions. In the CNS histamine serves as a neurotransmitter/modulator, promoting inter alia wakefulness. In the gastric mucosa, it acts as a mediator substance that is released from enterochromaf n-like (ECL) cells to stimulate gastric acid secretion in neighboring parietalcells(p.170). Histamine stored in blood basophils and tissue mast cells plays a mediator role in IgE-mediated allergic reactions (p.72). By increasing the tone of bronchial smooth muscle, histamine may trigger an asthma attack. In the intestines, it promotes peristalsis, which is evidenced in food allergies by the occurrence of diarrhea. In blood vessels, histamine increases permeability by inducing the formation of gaps between endothelial cells of postcapillary venules, allowing passage of fluid into the surrounding, tissue (e.g., wheal formation). Blood vessels are dilated because histamine induces release of nitric oxide from the endothelium (p.124) and because of a direct vasorelaxant action. By stimulating sensory nerve endings in the skin, histamine can evoke itching.

Receptors. Histamine receptors are coupled to G-proteins. The H1 and H2 receptors are targets for substances with antagonistic actions. The H3 receptor is localized on nerve cells and may inhibit release of various transmitter substances, including histamine itself.

Metabolism. Histamine-storing cells form histamine by decarboxylation of the amino acid histidine. Released histamine is degraded; no reuptake system exists as for norepinephrine, dopamine, and serotonin.

Antagonists. The H1 and H2 receptors can be blocked by selective antagonists.

H1-Antihistaminics. Older substances in this group (first generation) are rather nonspecific and also block other receptors (e.g.,

muscariniccholinoceptors). These agentsare used for the symptomatic relief of allergies (e.g., bamipine, clemastine, dimetindene, mebhydroline, pheniramine); as antiemetics (meclizine, dimenhydrinate; p.342); and as prescription-free sedatives/hypnotics (see p.220). Promethazine represents the transition to psychopharmaceuticals of the type of neuroleptic phenothiazines (p.232).

Unwanted effects of most H1-antihista- minics are lassitude (impaired driving skills) and atropine-like reactions (e.g., dry mouth, constipation). Newer substances (secondgeneration H1-antihistaminics) do not penetrate into the CNS and are therefore practically devoid of sedative effects. Presumably they are transported back into the blood bya P-glycoprotein locatedin the endotheliumof the blood–brain barrier. Furthermore, they hardly have any anticholinergic activity. Members of this group are cetirizine (a racemate) and its active enantiomer levocetirizine, as well as loratadine and its active metabolite desloratadine. Fexofenadine is the active metabolite of terfenadine, which may reach excessive blood levels when biotransformation (via CYP3A4) istoo slow; and which can then cause cardiac arrhythmias (prolongation of QT-interval). Ebastine and mizolastine are other new agents.

H2-Blockers (cimetidine, ranitidine, famotidine, nizatidine) inhibit gastric acid secretion, and thus are useful in the treatment of peptic ulcers (p.172). Cimetidine may lead to drug interactions because it inhibits hepatic cytochrome oxidases. The successor drugs (e.g., ranitidine) are of less concern in this respect.

Mast cell stabilizers. Cromoglycate (cromolyn) and nedocromil decrease, by an as yet unknown mechanism, the capacity of mast cells to release of histamine and other mediators during allergic reactions. Both agents are applied topically (p.338).