07.01.3 Sympathomimetics

The sympathomimetic drugs can be divided into those that do not show much selectivity for adrenoceptors, and these include adrenaline itself, ephedrine, and dopamine. The other sympathomimetics are those that show selectivity for one of the receptors, and hence only mimic some of the effects of the sympathetic nervous system. Selective sympathomimetics include dobutamine, salbutamol and salmeterol.

The most obvious way to mimic the effects of adrenaline is to use adrenaline as a medicine. When used as a medicine, adrenaline stimulates all types of adrenoceptors. Adrenaline is used clinically for its ability to cause an a-adrenoceptor mediated vasoconstriction. Adrenaline is used clinically as an additive to local anaesthetic preparations, where the local intense vasoconstriction decreases the absorption of the local anaesthetic to help limit the effect of the local anaesthetic to a local area. Without the adrenaline, the local anaesthetic will spread, and the action will no longer be local but spreading/widespread. Secondly, adrenaline can be applied topically to bleeding surfaces, where vasoconstriction reduces the surface for blood loss, and hence the blood loss. For instance, adrenaline can be applied to bleeding peptic ulcers during endoscopy.

Adrenaline is also used clinically for its ability to cause a b₁-adrenoceptor-mediated increase in heart rate and force. Thus, adrenaline is used intravenously in heart block and cardiac arrest.

Historically, adrenaline was used to cause a b₂-adrenoceptor-mediated bronchodilation. However, when adrenaline was used to alleviate bronchial asthma, it caused tachycardia due to stimulation the b₁-adrenoceptor of the heart, an unwanted effect in the treatment of asthma. What is needed in asthma is a selective b₂-adrenoceptor agonist that causes bronchodilation without tachycardia. Salbutamol is a selective b₂-adrenoceptor agonist, and is preferred to adrenaline in the treatment of asthma.

Adrenaline is used in the treatment of hypersensitivity reactions including anaphylaxis, where there is excessive vasodilation, which can lead to circulatory collapse, and excessive bronchoconstriction. This excessive vasodilation is overcome by adrenaline causing an α-adrenoceptor-mediated vasoconstriction and the excessive bronchoconstriction by a β₂-adrenoceptor-mediated bronchodilation.

In addition to having widespread effects and not being after oral administration, another limitation to the clinical use of adrenaline is that it is a very potent medicine, and it is difficult to moderate its effect. This has been overcome by developing less potent drugs such as ephedrine, which also have the benefit of being active after oral administration. Ephedrine, also known as pseudoephedrine, is a mixed acting amine, which means it has direct and indirect effects at receptors. The direct effect is that ephedrine is a weak agonist at a- and b-adrenoceptors, and the indirect effect is that ephedrine causes the release of noradrenaline. Most of the effect of ephedrine is probably mediated by the release of small amounts of noradrenaline (Figure 7.5).

Figure 7.5 Mechanism of action of ephedrine (Copyright QUT, Sheila Doggrell)

The noradrenaline causes an a-adrenoceptor-mediated vasoconstriction, which makes it useful as a nasal decongestant. In nasal congestion (bunged up nose) there is intense vasodilation, which collects lots of material. With vasoconstriction, the blood starts to move again and take away the collected material to clear the nose. Ephedrine also causes a small amount of b₂-adrenoceptor-mediated bronchodilation, which helps clear the chest. Thus, ephedrine is used to treat the nasal and lung congestion of the common cold.

Phenylephrine is a selective α-adrenoceptor agonist, which has no effect on β-adrenoceptors. Like pseudoephedrine, phenylephrine causes an α-adrenoceptor-mediated vasoconstriction to produce a decongestant effect. However, phenylephrine does not cause a β₂-adrenoceptor-mediated bronchodilation. Most people prefer ephedrine over phenylephrine for the treatment of a cold, probably because of the β₂-adrenoceptor-mediated bronchodilation.

Higher concentrations of dopamine act as a mixed acting amine (ephedrine-like). The direct action is being a weak agonist at a- and b- adrenoceptors, and the indirect action is releasing noradrenaline, with both of these actions leading to vasoconstriction. Dopamine is used intravenously in the treatment of circulatory shock (collapse) to produce vasoconstriction to maintain circulation.

Dobutamine is a selective b₁-adrenoceptor agonist, which means it has a greater effect at b₁-adrenoceptor than at other receptors. It is used to selectively mimic the effect of the sympathetic nervous system on the b₁-adrenoceptors of the heart. Thus, dobutamine is used to increase in heart force. Dobutamine is not active after oral administration, and is used I.v. in the treatment of circulatory shock to produce an increase in heart force (inotropic) response.

The last group of sympathomimetics are the selective b₂-adrenoceptor agonists such as salbutamol and salmeterol. Salbutamol and salmeterol have no effect at a-adrenoceptors, and are selective for b₂- over b₁-adrenoceptors. Salbutamol is the standard selective b₂-adrenoceptor agonist, whereas salmeterol is a long acting selective b₂- adrenoceptor agonist. Both medicines cause a b₂-adrenoceptor-mediated bronchodilation. Inhaled salmeterol is used to prevent bronchial asthma, whereas inhaled salbutamol is used in an asthma attack to overcome an attack, and can also be used intravenously in severe asthma attacks.

Adrenoceptor antagonists are used to prevent the effects of the sympathetic nervous system. Clinically used agents include the selective a₁-adrenoceptor antagonists, doxazosin and tamsulosin, the non-selective b-adrenoceptor antagonists propranolol, timolol and esmolol, and the selective b₁-adrenoceptor antagonists metoprolol and atenolol.