Adrenoceptor agonists
Examples – adrenaline, clonidine, dobutamine, dopamine, dopexamine, isoprenaline, noradrenaline
Note that β-adrenoceptor agonists are covered in more detail in Chapter 37.
Clinical uses
Adrenoceptor agonists are administered systemically for myocardial failure (inotropic), sepsis (vasoconstriction and inotropy), anaphylaxis, nasal congestion and bronchospasm. They may be administered peripherally to cause local vasoconstriction and so prolong the effects of local anaesthetics and reduce bleeding in the operative field. β2-Agonists are effective in the treatment of asthma when inhaled, which reduces systemic effects.
Adrenaline
Adrenaline has both α– and β-agonist effects and many applications. It is an inotrope and chronotrope but sensitises the myocardium to arrhythmias. The ventricles in particular become hyperexcitable. There is generalised vasoconstriction, but dilatation of skeletal muscle arterioles.
Dobutamine
Dobutamine is a non-selective β-agonist with both chronotropic and inotropic effects. It is usually used for its inotropic effect, but tachycardia may limit the dose. It causes some vasodilatation, and this may require concurrent treatment with an α-agonist such as noradrenaline.
Dopamine
Dopamine is an agonist at α1-, β– and dopamine receptors. The balance of these effects is dose-related. Initially only dopamine receptors are affected, but with increasing doses β-receptors and then α-receptors are also affected. Peripheral dopamine receptors are located in the renal arterioles and are responsible for vasodilatation. Dopamine is often used to maintain renal perfusion when this may be compromised. Increasing the dose recruits the β-receptors with their positive inotropic effect. This is limited by the onset of a tachycardia. Vasoconstriction (α1) may become a problem as the drug dose increases.
Dopexamine
Dopexamine is an agonist of β2-adrenergic and D1 and D2 dopamine receptors in the periphery. It also inhibits neuronal noradrenaline reuptake (uptake 1), so enhancing the β effects. It is a positive inotrope but has the principal effect of peripheral vasodilatation, especially of the splanchnic and renal arterioles. The resulting reduction in afterload improves cardiac output.
Isoprenaline
Isoprenaline is used in the treatment of bronchospasm, bradycardia and heart block. It is used to increase heart rate in complete heart block while electrical pacing is instituted. It is agonist at β1– and β2-receptors.
Noradrenaline
Noradrenaline is primarily an α1-agonist and causes vasoconstriction (although it does have some β-agonist effects). It is particularly useful in patients with septicaemic shock, as they have a pathological reduction in systemic vascular resistance resulting in hypotension and hypoperfusion due to diversion of blood away from essential organs. The inotropic effect, although small, may also help. It may cause a reflex bradycardia if hypotension is overcorrected.
Salbutamol
Salbutamol is an effective bronchodilator, used in both the treatment and prophylaxis of obstructive airway disease. It is a selective β2-agonist, and this minimises the undesirable effects such as tachycardia, although this β1 effect does still occur with higher doses. It also has a role as a uterine relaxant for the treatment of premature labour and before delivery during Caesarean section.
Clonidine
Clonidine is an α2-agonist used as a centrally acting antihypertensive agent that works by reducing noradrenaline release. Its role in preventing migraine is controversial. α2-receptors are located on the presynaptic membrane of noradrenergic neurones, and have also been found in the spinal cord and at peripheral nerve endings. Clonidine may prolong the effect of epidurally administered local anaesthetic agents, although it is not licensed for this route.
Metaraminol
Metaraminol tartrate has both α– and β-agonist effects, with the α effect predominating. It increases systemic and pulmonary vascular resistance and causes increased systolic and diastolic blood pressures. Heart rate decreases in response and some inotropy occurs, although overall cardiac output may fall or may not change. Cerebral and renal blood flow are reduced by the vasoconstriction, and during pregnancy uterine tone is increased. β effects increase blood glucose levels.
α-Adrenoceptor antagonists
Examples – alfuzosin, doxazocin, phenoxybenzamine, phentolamine, tamsulosin
Uses
α1-Adrenoceptor antagonists are used as antihypertensives and in benign prostatic hyperplasia.
Clinical effects
α-Blockade causes vasodilatation with reduced systemic vascular resistance and lowered blood pressure. There is a reflex increase in heart rate and cardiac output.
Phenoxybenzamine
Phenoxybenzamine is a haloalkylamine. The N-chloroethyl group binds covalently to part of the receptor. It therefore detaches from the receptor very slowly and behaves like a competitive irreversible antagonist. The recovery half-life is about 24 hours. Phenoxybenzamine is also an antagonist of acetylcholinergic, 5-hydroxytryptaminergic and histaminic receptors. Its primary effect is that of vasodilatation.
Labetalol
Labetalol is an antagonist at both α1– and β-receptors. The reflex tachycardia from the α-blockade is antagonised by the β-blockade. α-Blockade is more prominent when it is used intravenously, whereas β-blockade is the main effect when it is used orally.
β-Adrenoceptor antagonists
Examples: acebutolol, atenolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, sotalol
Mode of action
β-Adrenoceptors activate adenylyl cyclase. There are two subtypes of β-receptor (β1 and β2). In general, β1-receptors tend to be excitatory and β2-inhibitory. β-Adrenoceptor antagonists with a specific affinity for β1-receptors alone are called selective, and those also affecting β2-receptors are called non-selective. Even those classified as selective still have some β2-antagonism. Some β-blockers are partial agonists (intrinsic sympathomimetic activity), so that at low dose there is increasing agonism as the dose increases, but a plateau is reached and there is antagonism of circulating catecholamines. They may have an advantage over the others in minimising bradycardia, reducing heart failure and maintaining perfusion to the extremities. The membrane-stabilising effect that some β-blockers have is, however, of little clinical importance. Figure 35.6 shows the selectivity and partial agonist properties of the β-blockers.
| Antagonist | Partial agonist | |
|---|---|---|
| Selective | Atenolol Betaxolol Bisoprolol Esmolol Metoprolol Nadolol | Acebutalol Alprenolol |
| Non-selective | Propranolol Sotalol Timolol | Celiprolol Oxprenolol Pindolol |
Uses
β-Blockers are used in the treatment of angina, hypertension, tachyarrhythmias, anxiety, glaucoma, migraine, phaeochromocytoma and thyrotoxicosis.
Clinical effects
The clinical effects (Figure 35.7) are predictable from knowledge of receptor locations. The important effects for clinical use are those of negative inotropy and negative chronotropy, which reduce blood pressure and myocardial work. Coronary blood flow is reduced, but this effect is less than the reduction in myocardial work. These drugs are particularly effective when sympathetic tone is increased, for example following myocardial infarction, but care must be taken not to block a protective inotropic effect in incipient heart failure. The undesirable effects include bradycardia, bronchoconstriction, sleep disturbance, hypoglycaemia (especially with exercise) and cold extremities.
| Peripheral |
Cardiovascular system
|
Respiratory system
|
Renal system
|
Metabolic
|
Eye
|
| Central |
|
β-Blockers (whether selective or not) should be avoided in asthmatic patients. They should be used with caution in diabetes, peripheral vascular disease and heart failure. Calcium antagonists with negative inotropic effects (verapamil and diltiazem) act synergistically with β-blockers to cause hypotension, bradycardia and conduction defects, and they should not be administered contemporaneously.
Atenolol, celiprolol, nadolol and sotalol are very water-soluble and therefore penetrate the brain poorly and are primarily excreted in the urine. In general, the β-blockers are well absorbed orally, but the first-pass effect is particularly high with alprenolol, propranolol, metoprolol, oxprenolol and timolol. Bisoprolol and sotalol have a high bioavailability.
Atenolol
Atenolol is a popular selective β-blocker for the control of essential hypertension. In the clinical setting, patient compliance with the treatment is often apparent from a relatively slow heart rate. Bioavailability is 50% and protein binding is low. Atenolol is highly water-soluble and is largely excreted unchanged in the urine.
Esmolol
Esmolol hydrochloride is a short-acting β1-adrenoceptor antagonist, and class II antiarrhythmic. This aryloxypropanolamine is rapidly hydrolysed to a low-activity acid by red cell esterases and has a half-life of only 9 minutes. It is used in the acute management of supraventricular tachycardias, hypertension and myocardial infarction, and is an option for suppression of the hypertensive response to laryngoscopy and intubation.
Propranolol
Propranolol is a non-selective β-blocker with no intrinsic sympathomimetic activity. It has been largely superseded by selective antagonists but still has a role in the management of phaeochromocytoma (in conjunction with α-blockade), thyrotoxicosis and crisis, acute hypertension and tachyarrhythmias. Propranolol has a high first pass with a bioavailability of only 10–30%. It is lipid-soluble and highly protein-bound (90–95%).
Drugs interfering with synthesis, storage, release and metabolism of catecholamines
Examples – bretylium, carbidopa, guanethidine, methyldopa, reserpine
A few drugs act by interfering with the metabolic elements of the catecholamines rather than with receptor interactions. While not widely used now, as they lack specificity, these agents merit brief consideration.
Synthesis
Carbidopa inhibits dopa decarboxylase and so prevents the formation of dopamine, the first catecholamine in the chain of synthesis. Carbidopa does not cross the blood–brain barrier and is therefore used to minimise the peripheral effects of levodopa (l-DOPA) used in the treatment of Parkinsonism. The antihypertensive agent methyldopa is a false substrate for dopa decarboxylase and dopamine hydroxylase and results in the synthesis of a false transmitter – methyl noradrenaline. This is ineffective, and as it is not metabolised by monoamine oxidase it accumulates within the nerve terminal and displaces the true neurotransmitter, which becomes depleted.
Storage
Reserpine blocks the uptake and reuptake of noradrenaline, dopamine and 5-hydroxytryptamine in the neuronal terminals. The neurotransmitter accumulates within the cytoplasm where MAO inactivates it and transmitter levels fall. It affects both the sympathetic and central nervous systems but has been superseded by drugs that are more specific.
Release
Guanethidine was originally used as an antihypertensive but is now used in the management of chronic pain. It is transported by the uptake 1 mechanism and accumulates in the nerve terminals. Initially it causes release of noradrenaline from the vesicles and then inhibits release of the diminishing levels of noradrenaline. Bretylium has a similar mode of action. Guanethidine is used to treat reflex sympathetic dystrophy by IV regional sympathetic block (chemical sympathectomy), in which guanethidine is injected intravenously into an isolated limb.
Direct-acting vasodilating agents
Calcium channel antagonists
Examples – amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine
The calcium channel antagonists are covered in detail in Chapter 36. This is a mixed group of drugs having in common the blockade of various calcium ionophores in cell and intracellular membranes. These vasodilators relax vascular smooth muscle preferentially and dilate coronary and other arterial smooth muscle. They can be used in conjunction with β-blockers. Amlodipine, felodipine, nicardipine and nifedipine are used to treat both hypertension and angina. Isradipine and lacidipine are only useful in the treatment of hypertension. Nimodipine has a specificity for cerebral arterioles and is used to treat vascular spasm following subarachnoid haemorrhage or neuroradiological instrumentation.
Organic nitrates, nitrites and related drugs
Examples – glyceryl trinitrate, isosorbide di- and mononitrate, nitric oxide, nitroprusside
Uses
These are direct-acting vascular smooth muscle relaxants that are used to control and reduce blood pressure and to alleviate angina.
Mode of action
Both organic nitrates (NO3−) and sodium nitroprusside act in a similar way. Having diffused from the vascular lumen through to the smooth muscle they are converted to nitrites (NO2–) by reacting with –SH groups (thiols) in the tissues. Hydrogen ions within the cells then react with the nitrite to produce nitric oxide (NO). This in turn reacts with more thiols in the muscle cell to produce nitrosothiols. These stimulate guanylyl cyclase to convert guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) in a comparable way to adenylyl cyclase. The cGMP then relaxes the smooth muscle. Nitric oxide may be administered by inhalation to selectively dilate pulmonary arterioles. It mimics the physiological mediation by the vascular endothelial cells of a number of circulating autacoids such as bradykinin, which stimulate nitric oxide synthase to convert arginine to citrulline and nitric oxide. This nitric oxide (formerly identified as endothelium-derived relaxing factor, EDRF) diffuses into the muscle cell, where it has its effect.
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