P2-Sympathomimetics

Bronchodilators. Narrowing of bronchioles raises airway resistance, e.g in bronchial or bronchitic asthma Several substances that are employed as bronchodilators are described elsewhere in more detail P2-sympathomimetics (p. 84, given by pulmonary, parenteral, or oral route), the methylxanthine theophylline (p. 326, given parenterally or orally), as well as the parasympatholytic ipratropium (pp. 104, 107, given by inhalation). 

The Austrian pharmacologist Heribert Konzett (1912-2004) had discovered in 1940 isoprenaUne, which should become the prototype of p-selective sympathomimetics. Due to its bronchodilatory properties, but without causing hyper-tention, it was considered the drug of choice to treat asthmatic attacks. With almost equally strong effect on pj- and p2-receptors, it was of concern, that isoprenaline acts as a very potent cardiac stimulant. Further structural optimisation then led to more selective pj-sympathomimetics, like dobutamine, for the treatment of heart failure and cardiogenic shock, while selective p2-sympathomimetics were aimed at safer therapies of bronchial asthma. 

P2-Sympathomimetics can be grouped into different structural clusters, which aU take into account, that modification of the catechol moiety affects... 

Derivatives of phenylethanolamine substituted by a phenolic hydroxyl on the para position have been known for some time to exhibit p-adrenergic agonist activity. As a consequence of this property, the compounds have proven useful as bronchodilators for the treatment of asthma (see Chapter 3). Since such sympathomimetic drugs tend to have undesired activity on the cardiovascular system in addition to the desired activity on the bronchii, considerable work has been devoted to the preparation of compounds that would show selectivity for the adrenergic receptors (P2) that predominate in the lung. Attachment of the side chain to a heterocyclic aromatic phenol has been one avenue that has shown promise for achieving this selectivity. 

While the inhibition of noradrenaline re-uptake exerts predominantly an a-adrenergic effect, a selective jS-adrenergic effect can not be obtained by such an indirect mechanism. All selective /3-sympathomi-metics activate the receptors, P -, P2- or both sub-types, directly. The first pure jS-sympathomimetic in clinical use was isoproterenol which is structurally identical to adrenaline except the methyl-moiety at the N-position in the side-chain is replaced by an isopropyl-group. All effects produced by isoproterenol are due to either P -or 62-adrenoceptor stimulation tachycardia, increased stroke volume, decreased vascular resistance, broncho dilatation and, in pregnancy, uterus relaxation. The metabolic effects of isoproterenol are less pronounced than those of adrenaline. 

Isoproterenol, a synthetic sympathomimetic amine acting selectively at both Pi - and P2-adrenoceptors, is also able to induce panic attacks in a subset of patients suffering from panic disorder. There is, however, a discrepancy in the findings, and the rehability and mechanisms of isoproterenol-induced panic remain to be clarified. It should also be emphasized that isoproterenol is not able to cross the blood-brain barrier. 

Timolol is a noncardioselective P-blocker without intrinsic sympathomimetic activity (ISA). Antagonism of the P2-adrenoceptor at the ciliary body is primarily responsible for the ocular hypotensive efficacy of timolol. 

Answer D. The effectiveness of labetalol in the management of hypertension and in severe hypertensive states appears to be due to a combination of antagonistic actions at both alpha and beta adrenoceptors. Labetalol is not a P selective blocking agent (unlike atenolol and metoprolol), and (unlike pindolol and acebutolol) it lacks intrinsic sympathomimetic activity. Labetalol is available for both peroral and parenteral use unfortunately, it blocks p2 receptors in bronchiolar smooth muscle. 

Parker and Kirk (P2), in 1961, attempted the GLC separation of barbiturates as the free acids, using a solid support of acid-washed firebrick (apparently unsilanized). They found that the retention time varied with sample size. In a later article, Parker et al. (P3) described the use of acid-washed Chromosorb W coated with either 5% SE-30 or 1% Carbowax 20 M in an attempt to provide a gas chromatographic screening procedure for barbiturates, alkaloids, sympathomimetic amines, and tranquilizers. Their conditions probably represent a compromise, with the result that their column was not necessarily the best that could have been prepared for resolution of mixtures containing only barbiturates. 

The actions of labetalol on both a, and p receptors contribnte to the fall in blood pressure observed in patients with hypertension, a -Receptor blockade leads to relaxation of arterial smooth muscle and vasodilation, particularly in the npright position. The Pj-blockade also contributes to a fall in blood pressure, in part by blocking reflex sympathetic stimnlation of the heart. In addition, the intrinsic sympathomimetic activity of labetalol at P2 receptors may contribnte to vasodilation. 

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