Adrenoceptors sympathomimetics

As of the mid-1990s, use of MAOIs for the treatment of depression is severely restricted because of potential side effects, the most serious of which is hypertensive crisis, which results primarily from the presence of dietary tyramine. Tyramine, a naturally occurring amine present in cheese, beer, wine, and other foods, is an indirecdy acting sympathomimetic, that is, it potently causes the release of norepinephrine from sympathetic neurons. The norepinephrine that is released interacts with adrenoceptors and, by interacting with a-adrenoceptors, causes a marked increase in blood pressure the resultant hypertension may be so severe as to cause death. 

Some P-adrenoceptor blockers have intrinsic sympathomimetic activity (ISA) or partial agonist activity (PAA). They activate P-adrenoceptors before blocking them. Theoretically, patients taking P-adrenoceptor blockers with ISA should not have cold extremities because the dmg produces minimal decreases in peripheral blood flow (smaller increases in resistance). In addition, these agents should produce minimal depression of heart rate and cardiac output, either at rest or during exercise (36). 

P-Adrenoceptor blockers for the treatment of hypertension include (/) the cardioselective P -adrenoceptor blockers without intrinsic sympathomimetic activity (ISA), ie, atenolol (Table 3), bisoprolol (Table 3), and metoprolol (Table 1) (2) the cardioselective with ISA, ie, acebutolol (Table 1) (J) the noncardioselective without ISA, ie, propranolol (Table 1) and timolol [26839-75-8] C23H24N4O2S and (4) the noncardioselective with ISA, ie, oxprenolol [6452-71-7] C 3H23N03, and pindolol. 

Hoffman, B.B., Adrenoceptor-activating and other sympathomimetic drugs, in Basic and Clinical Pharmacology, 8th ed., Katzung, B.G., Ed., Lange Medical Books/McGraw-Hill, New York, 2001, chap. 9. 

Esmolol hydrochloride is a competitive p-adrenergic receptor antagonist it is selective for pT adrenoceptors. In contrast to pindolol, esmolol has little intrinsic sympathomimetic activity, and it differs from propranolol in that it lacks membrane stabilizing activity Of all of the p-adrenergic blocking drugs, this compound has the shortest duration of action because it is an ester, it is hydrolyzed rapidly by plasma esterases and must be used by the intravenous route Esmolol is approved only for the treatment of supraventricular arrhythmias... 

Knowledge of structure-activity relationships has permitted the synthesis of sympathomimetics that display a high degree of selectivity at adrenoceptor subtypes. 

Absence of one or both aromatic hydroxyl groups is associated with an increase in indirect sympathomimetic activity, denoting the ability of a substance to release norepinephrine from its neuronal stores without exerting an agonist action at the adrenoceptor (p. 88). 

Adrenoceptors are mostly in the close vicinity of the synaptic cleft whereas 02-adrenoceptors appear to be localized in some distance to this structure. A great number of sympathomimetics and sympa-tholytics exist which display different affinities towards the different adrenoceptor subtypes. This is of considerable therapeutic relevance. 

In contrast to the highly specific structural requirement for ligands at the various adrenoceptor subtypes the re-uptake mechanism (into the axon and into the vesicle) are less discriminative. Compounds without hydroxyl moieties at the phenyl ring have no affinity towards the adrenoceptors but serve as a substrate for the re-uptake mechanisms, thereby competing with noradrenaline and as a consequence increasing its concentration in the synaptic cleft. Drugs enhancing the sympathetic tone by this mechanism are called indirect sympathomimetics, for example tyramine, ephedrine, amphetamine. 

The hydroxyl groups of the phenyl ring are a prerequisite for the activation of all adrenoceptors, if both are absent the molecule has only an indirect sympathomimetic effect (see Fig. 5). Indirect sympathomimetics only have a -, a2 and -adrenoceptor activity since they act via an increase of the noradrenaline concentration in the synaptic cleft. If the methyl-group at the N-position of adrenaline is substituted by a longer or more bulky moiety the molecule gains affinity for the and loses affinity for O -adrenoceptors. An isopropyl moiety is already the optimum for the affinity towards 0-adrenoceptors (isoprenaline), larger substituents enhance only the binding to the 2-subtype (for example fenoterol). 

The indirect sympathomimetic drugs can be used clinically for systemic or local vasoconstriction. Since the mechanism is an increase in the noradrenaline concentration there are always jSi-adrenoceptor-mediated effects like tachycardia and extrasystoles. Since the re-uptake of noradrenaline is necessary to sufficiently refill the axonal vesicles, a frequent use of indirect sympathetic drugs results in a loss of efficacy by transmitter exhaustion. This phenomenon of use-dependent loss of effect is called tachyphylaxis. 

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. 

Due to the numerous indications for these type of drugs a large number of compounds have been introduced into therapy. Differences between these drugs concern their affinity profile towards the Pi-and j82-adrenoceptors, the lipophilicity and the ability to partially activate the receptor (intrinsic sympathomimetic activity, ISA). One isomer of the racemic mixture of labetalol and carvedilol are a-blocker as well. Although this might be therapeutically useful in the treatment of conditions like hypertension and heart failure, there is no real evidence for a contribution of this property to the overall beneficial effect of these compounds. 

Pindolol, oxprenolol, acebutolol and alprenolol are /3-blocker ISA. A weak sympathomimetic effect can be seen in the heart if almost all /3-adrenoceptors are occupied by these compounds. The advantage of ISA might be that a basal /3-adrenergic stimulus is left. In some vessel beds a reduction of the vascular activity and thereby a reduction in resistance has been observed with pindolol which might be beneficial in the therapy of hypertension. The pharmacodynamic and -kinetic properties of some frequently used jS-blocker are shown in Table 2. 

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. 

Esmolol (Brevibloc) is a short-acting intravenously administered Pi-selective adrenoceptor blocking agent. It does not possess membrane-stabilizing activity or sympathomimetic activity. 

Table 8.4 summarises the currently available 3-adrenoceptor antagonists, their relative 31 selectivity, intrinsic sympathomimetic activity, and the availability of intravenous formulations. 

Concomitant use with sympathomimetic drugs, p-adrenoceptor antagonists, calcium channel-entry blockers and other cardioactive drugs may result in bradyarrhythmias, bigemini, or tachyarrhythmias. Cardiac rhythm should be closely monitored and drug dosages carefully adjusted. Digoxin is mainly excreted by the kidneys and plasma levels should be closely monitored in patients with acute renal failure and in those whose renal function is compromised. 

Dopexamine is a synthetic catecholamine with direct and indirect sympathomimetic activity. The indirect effect is caused by potent inhibition of neuronal noradrenaline reuptake. It is a potent 32-adrenoceptor agonist with much less (31- than 32-receptor activity. It also has significant dopaminergic DAl-receptor activity, with only minimal activity at DA2 receptors and no o-adrenergic activity. 

Ephedrine is a sympathomimetic amine with direct and indirect effects on a, pi and 32 adrenoceptors 31=32>o). 

Phosphodiesterases are a group of enzymes that, among other actions, hydrolyse cAMP. Phosphodiesterase inhibitors are selective for phosphodiesterase III (PDE-III) isoenzyme present in the heart. They prevent the degradation of cAMP, thereby increasing its intracellular concentration (Figure 8.4). This leads to an increase in the intracellular concentration of Ca2+ and an increased contractility and heart rate. PDE-III inhibitors have no adrenoceptor agonistic activity and therefore can be used in combination with other sympathomimetic drugs. They also increase cAMP levels in vascular smooth muscle, but this results in lower intracellular Ca2+ concentrations and thus vasodilatation. 

Sympathomimetic effects (from NA re-uptake inhibition) and antimuscarinic effects can cause a sinus tachycardia. Postural hypotension may occur as a result of sympatholytic al-adrenoceptor antagonism. With overdoses of these drugs, there is a reduced re-uptake of catecholamines, resulting in arrhythmias and hypertension. Tricyclic compounds have a high... 

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