07.01.5 β-Adrenoceptor Antagonists
Figure 7.7 Propranolol and exercise (Copyright QUT, Sheila Doggrell)
Adrenaline b2-adrenoceptor mediated vasodilation is also inhibited by b-blockers. With decreased vasodilation, there is decreased heat delivered to the extremities (toes and fingers), and these may become cold.
In addition to problems because of adverse effects, non-selective b-blockers are contraindicated in asthma and diabetes. On the lung, adrenaline secreted from the adrenal medulla, acts at the b2-adrenoceptors to relax the bronchial smooth muscle to give a bronchodilation. Propranolol prevents this happening, reducing the bronchodilation to effectively give a bronchoconstriction. People with normal lung function can tolerate this, and there is no serious effect. In contrast, in subjects with asthma, the bronchoconstriction observed with propranolol can precipitate an attack of asthma. Consequently, non-selective b-blockers are contraindicated in asthmatics. Most b1-blockers are selective not specific for b1-adrenoceptors - they have some effects at b2-adrenoceptors. Consequently, selective b1-adrenoceptor antagonists are also contraindicated in asthmatics.
When a person becomes hypoglycaemic, this is signal for the release of adrenaline, which stimulates the b2-adrenoceptors of the liver to promote both the conversion of glycogen and of proteins to glucose to overcome the hypoglycaemia (Figure 7.8).
Figure 7.6 Propranolol and heart and kidney (Copyright QUT, Sheila Doggrell)
On the kidney, noradrenaline stimulates b1-adrenoceptors to cause the activation of the renin-angiotensin-aldosterone system, with angiotensin II causing vasoconstriction, and aldosterone causing salt and water retention (Figure 7.5). Propranolol prevents this from happening effectively reducing the activity of the renin-angiotensin-aldosterone system. As angiotensin II is a potent vasoconstrictor, and aldosterone promotes salt and water retention, both of which increase blood pressure, there removal with propranolol leads to a decrease in blood pressure.
Overall, propranolol has two mechanisms to decrease blood pressure. Firstly, propranolol acts on the heart to decrease cardiac out and, hence, to decrease blood pressure. Secondly, propranolol acts on the kidney to decrease the activity of the renin-angiotensin-aldosterone system, and hence, to decrease blood pressure. This suggests that b-blockers should be useful in the treatment of hypertension, and they are but there are a few problems with the b-blockers.
The first problem with using non-selective b-blockers in hypertension is that they have adverse effects on the cardiovascular system. Subjects with hypertension do not feel unwell, and are very intolerant of taking drugs that give adverse effects. Propranolol adversely affects exercise. When you exercise, there is an activation of the sympathetic nervous system, release of noradrenaline, and increased heart rate and force, which allows an increased exercise tolerance (Figure 7.7). Propranolol inhibits this to give a decreased exercise capacity, which is disconcerting for exercise junkies who have become hypertensive, and prescribed b-blockers.
Propranolol and timolol are non-selective b-adrenoceptor antagonists. On the heart, noradrenaline stimulates b1-adrenoceptors to increase heart rate and force. Propranolol prevents this from happening, and effectively gives a decrease in heart rate and force (Figure 7.6).
Figure 7.8 Hypoglycaemia stimulation of glucose production (Copyright QUT, Sheila Doggrell)
Propranolol inhibits this production of glucose, but this is not usually a problem in non-diabetics, as there are other ways to control glucose levels. However, when metabolism is compromised or being treated in diabetes, the ability of b-blockers to inhibit these metabolism pathways can be a problem, and the diabetic taking b-blockers can remain or become hypoglycaemic.
The b1-selective adrenoceptor antagonists, metoprolol and atenolol, are selective, not specific, for b1-adrenoceptors, and have some effects at b2-adrenoceptors. The selective b1-blockers are preferred to propranolol in the treatment of hypertension, but not really for any benefits relating to the selectivity, more because they have less centrally-β-adrenoceptor mediated side effects e.g. nightmares, due to a lesser ability to get into the central nervous system than propranolol. Metoprolol and atenolol are, like the non-selective b-blockers, contraindicated in asthmatics, but (unlike propranolol) can be used with caution in subjects with diabetes.
Esmolol was developed as a short acting non-selective b-adrenoceptor blocker for intravenous use in critically ill patients with hypertensive emergency. In some critically ill patients, blood pressure fluctuates widely. Esmolol is rapidly metabolised. In critically ill patients who are hypertensive, esmolol is administered by continuous intravenously to reduce blood pressure. If the blood pressure suddenly dips, the esmolol infusion is stopped, and the b-adrenoceptor blockade is quickly removed.
On the eye, adrenaline stimulates b2-adrenoceptors to promote aqueous humour formation, and the more aqueous humour is in the eye, the higher the pressure is in the eye. Timolol is a competitive reversible antagonist at these receptors, and is used locally to prevent the production of aqueous humour, and decrease the pressure in the eye, making it useful in glaucoma, where there is an increased intraocular pressure. Glaucoma is the leading cause of irreversible blindness. It is usually associated with elevated pressure in the eye (elevated intraocular pressure). This pressure leads to damage to the optic nerve (optic neuropathy), which in turn leads to loss of vision, starting with peripheral vision. Timolol is a non-selective b-blockers, which potentially has the potential to block all the b-adrenoceptors in the body, but by applying timolol directly to the eye, we limit its effects to a local area.
The effects of the sympathetic nervous system are often opposed by the other part of the autonomic nervous system, the parasympathetic nervous system.