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116 Biogenic Amines

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.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

 

 

 

 

 

 

 

Dopamine

117

A. Dopamine actions as influenced by drugs

 

 

 

 

 

 

 

 

 

 

 

Dopaminergic neuron

 

Release and

 

H3C–O

 

 

 

Neuronal

–COOH

 

 

 

 

 

reuptake

 

 

 

 

 

 

 

 

inactivation

 

 

 

 

 

 

 

 

 

 

 

COMT

 

HO

 

 

 

MAO

 

 

Catechol

 

HO

 

CH2

CH2

NH2

Monoamine

 

 

O-methyltransferase

 

oxidase

 

 

 

 

 

 

 

 

 

 

 

 

 

Dopamine

 

 

 

Receptor

 

 

D1-like

 

D2-like

 

 

subtypes

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

D1

D5

 

D2

D3 D4

 

 

Drugs

 

 

 

 

 

 

 

 

 

Antiparkinson agents

Inhibitors of

 

Antiemetics

Neuroleptics

 

neurosecretion

 

 

 

 

 

 

 

 

 

L-Dopa

Dopamine

 

D2-agonists

 

 

 

D2-antagonists

 

(precursor)

D2-agonists

 

 

 

 

 

 

 

 

 

 

 

 

AH

 

 

 

Area

 

 

Striatum

 

 

 

 

 

 

 

 

 

 

 

D2-an-

 

post-

 

 

 

 

 

 

 

 

 

 

 

 

 

tagonists

rema

 

S. nigra

Prolactin

 

D2

 

Emesis

Schizophrenia

 

B. Dopamine as a therapeutic agent

 

 

Circulatory

 

 

shock with

Dopamine

 

impaired

 

renal blood

 

 

flow

 

 

 

 

Toxic

Dose

β 1

α 1

D1

Receptors

 

 

Effect

 

 

Blood flow

Stimulation

Vasoconstriction

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

118 Biogenic Amines

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).

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

 

 

 

 

 

 

 

 

 

 

 

 

Histamine

119

A. Histamine actions as influenced by drugs

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Entero-

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

chromaffin-

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

like cell

 

 

 

 

Alertness

 

C

 

C

2 NH2

 

 

 

 

 

 

 

 

 

 

 

 

N

2

HCl

 

 

 

 

 

 

H1

 

 

H

 

H

 

 

 

 

 

 

 

 

 

 

 

secretion

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

 

 

 

 

 

 

Histamine

 

 

 

 

 

 

 

 

 

 

 

 

 

H

Parietal

 

Histamine

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

cell

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H2

 

 

CNS

 

 

 

 

 

 

 

 

 

 

Stomach

 

 

 

 

 

 

 

 

 

 

H1

 

 

H1

H1

 

H2

 

H1

 

 

 

 

 

 

 

 

 

 

 

 

via

direct

 

 

 

 

 

 

 

 

 

 

 

 

 

 

NO

 

 

Itching

Mast cell

 

 

 

 

Broncho-

 

Peristalsis

Dilation

 

 

 

 

 

 

 

 

constriction

 

Permeability

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Inhibition of release:

 

 

 

 

 

 

 

 

 

 

 

 

“Mast cell stabilization”;

 

 

 

 

 

 

 

 

 

 

 

e.g., cromolyn

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Bronchial tree

 

Bowel

Vasculature

 

Skin

 

 

 

 

 

 

 

Receptor antagonists

 

 

 

 

 

 

 

H1- Antihistaminics

 

 

 

H2-Antihistaminics

 

 

 

1. Generation

 

 

 

 

 

 

 

 

 

Caution:

 

 

 

 

 

 

CH3

 

 

 

 

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Drug

 

 

 

CH O

 

CH2

CH2

N

 

 

 

 

HN

CH2

S

 

interaction

 

 

 

 

 

 

CH3

 

 

 

 

CH3

 

(CH2)2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Diphenhydramine

 

 

 

 

Cimetidine

NH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

C

NHCH3

 

 

CNS

 

 

 

mACh

 

 

 

Inhibition of

 

N

C

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

receptor

 

 

 

cytochrome

 

 

 

 

 

 

Sedation

 

 

antagonist

 

 

 

oxidases

 

 

 

 

 

 

Cl

 

2. Generation

 

 

 

 

H3C

 

 

 

 

 

 

 

 

 

 

 

N CH2

 

 

CH2

S

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

H3C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(CH2)2

H

C

N

N

CH2

CH2

O

CH2

COOH

 

 

 

 

 

 

NH

 

 

 

 

Cetirizine

 

 

 

 

 

 

Ranitidine

C

NHCH3

 

 

 

 

 

 

 

 

 

 

CH

NO2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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