re-uptake into the nerve terminal

 diffusion into the circulation

 enzymatic destruction.

Adrenaline: Adrenaline comprises 80–90% of adrenal medullary catecholamine content and is also an important CNS neurotransmitter. It is a powerful agonist at both α- and β-adrenergic receptors, being slightly less potent than noradrenaline at α₁-receptors but more potent at β-receptors. It is the treatment of choice in acute allergic (anaphylactic) reactions and is used in the management of cardiac arrest and shock, and occasionally as a bronchodilator. Except in emergency situations, i.v. injection is avoided because of the risk of inducing cardiac arrhythmias. Subcutaneous administration produces local vasoconstriction and so smoothes out its own effect by slowing absorption.

The effects of adrenaline on arterial pressure and cardiac output are dose-dependent. Although both α- and β-receptors are stimulated, β₂-vasodilator effects are most sensitive. β₁-Mediated effects cause marked increases in heart rate and contractility, cardiac output and systolic pressure. In low dosage, vasodilatation in skeletal muscle and splanchnic arterioles (β₂) may predominate over α-mediated vasoconstriction in skin and renal vasculature; systemic vascular resistance and diastolic pressure may decrease, pulse pressure widens, but mean arterial pressure remains stable. At higher doses, α-mediated vasoconstriction becomes more prominent in venous capacitance vessels (increasing venous return) and the precapillary resistance vessels of skin, mucosa and kidney (increasing peripheral resistance). Systolic pressure increases further, but cardiac output may decrease. Adrenaline causes marked decreases in renal blood flow, but coronary blood flow is increased. In contrast to other sympathomimetics, adrenaline has significant metabolic effects. Hepatic glycogenolysis and lipolysis in adipose tissue increase (β₁ and β₃ effects), and insulin secretion is inhibited (α₁ effect) so that hyperglycaemia occurs.

Adrenaline 0.5–1 mg i.m. (0.5–1.0 mL of 1:1000 solution) or 100 μg increments i.v. to a dose of 1 mg (1–10 mL of a 1:10 000 solution) is used to treat acute anaphylactic reactions. Adrenaline is important in the management of cardiac arrest (in doses of 1 mg i.v., repeated every 3–5 min), mostly because of its α effects; widespread systemic vasoconstriction occurs, increasing aortic diastolic pressure, and coronary and cerebral perfusion. Pure α-agonists are less effective than adrenaline in the management of cardiac arrest, and the β₂ effects of adrenaline may contribute to improved cerebral perfusion. In emergency situations, it may also be administered via the tracheal route, in doses of 2–3 mg diluted to a volume of 10 mL. It is effective by aerosol inhalation in bronchial asthma but has been superseded by selective β₂-agonists (see below). Unlike indirect-acting sympathomimetics which cause release of noradrenaline, tachyphylaxis should not occur with adrenaline. Adrenaline is also used as a topical vasoconstrictor to aid haemostasis and is incorporated into local anaesthetic solutions to decrease systemic absorption and prolong the duration of local anaesthesia.

Noradrenaline: Noradrenaline acts as a potent arteriolar and venous vasoconstrictor, acting predominantly at α-receptors, with a slightly greater potency there than adrenaline. It is also an agonist at β-receptors, but β₂ effects are not apparent in clinical use. Infusions of noradrenaline increase venous return, systolic and diastolic systemic and pulmonary arterial pressures, and central venous pressure. Cardiac output increases but heart rate decreases because of baroreflex activity. At higher doses, the α-mediated effects of widespread intense vasoconstriction overcome β₁ effects on cardiac contractility, leading to a decrease in cardiac output at the cost of increased myocardial oxygen demand in conjunction with reductions in renal blood flow and glomerular filtration rate. Its principal use is in the management of septic shock when systemic vascular resistance is low.

Dopamine: Dopamine is the natural precursor of adrenaline and noradrenaline. It stimulates both α- and β-adrenergic receptors in addition to specific dopamine DA₁-receptors in renal and mesenteric arteries. Dopamine has a direct positive inotropic action on the myocardium via β-receptors and also by release of noradrenaline from adrenergic nerve terminals. The overall effects of dopamine are highly dose-dependent. In low dosage (< 3 μg kg^–1 min^–1), renal and mesenteric vascular resistances are reduced by an action on DA₁-receptors, resulting in increased splanchnic and renal blood flows, glomerular filtration rate and sodium excretion. At doses of 5–10 μg kg^–1 min^–1, the increasing direct β-mediated inotropic action predominates, increasing cardiac output and systolic pressure with little effect on diastolic pressure; peripheral resistance is usually unchanged. At doses > 15 μg kg^–1 min^–1, α-receptor activity predominates, with direct vasoconstriction and increased cardiac stimulation (similar to noradrenaline). Renal and splanchnic blood flows decrease, and arrhythmias may occur. Dopamine receptors are widely present in the CNS, particularly in the basal ganglia, pituitary (where they mediate prolactin secretion) and the chemoreceptor trigger zone on the floor of the fourth ventricle (where they mediate nausea and vomiting). Recently, dopamine infusions have been associated with decreased prolactin secretion, and the use of ‘prophylactic’ dopamine infusions in an attempt to preserve renal function in perioperative or critically ill patients has declined.

Isoprenaline: Isoprenaline is a potent β₁– and β₂-agonist, with virtually no activity at α-receptors. It acts via cardiac β₁-receptors, and at β₂-receptors in the smooth muscle of bronchi, the vasculature of skeletal muscle and the gut. After intravenous infusion, heart rate increases and peripheral resistance is reduced. Cardiac output may increase because of increased heart rate and contractility but effects on arterial pressure are variable. Isoprenaline also reduces coronary perfusion pressure, increases myocardial oxygen consumption and causes arrhythmias. Other β₂-mediated effects include relaxation of bronchial smooth muscle and stabilization of mast cells. It has been superseded for use in the treatment of severe asthma by newer specific β₂-agonists with fewer cardiac effects. Its current indication is as an infusion in the treatment of bradyarrhythmias or atrioventricular heart block associated with low cardiac output (e.g. following acute myocardial infarction) because it increases heart rate and conduction by a direct action on the subsidiary pacemaker. This indication is usually an interim measure before insertion of a temporary pacing wire.

Dobutamine: Dobutamine is primarily a β₁-agonist, with moderate β₂– and mild α₁-agonist activity, and no action at DA-receptors. Its primary effect is an increase in cardiac output via increased contractility (β₁ effect) augmented by a reduction in afterload. Heart rate also increases (β₂ effect). Systolic arterial pressure may increase but peripheral resistance is reduced or unchanged. There is no direct effect on venous tone or renal blood flow but preload may decrease and urine output and sodium excretion increase as a consequence of the increased cardiac output. Dobutamine increases SA node automaticity and conduction velocity in the atria, ventricles and AV node, but to a lesser extent than isoprenaline. Dobutamine infusion produces a progressive increase in cardiac output which is greater than with comparable doses of dopamine, although arterial pressure may remain unchanged. At higher doses, tachycardia and arrhythmias may occur, but dobutamine has less effect on myocardial oxygen consumption compared with other catecholamines. Dobutamine is widely used to optimize cardiac output in septic shock, often in combination with noradrenaline. It is also used alone or in combination with vasodilator drugs in heart failure when peripheral resistance is high, and to increase heart rate and cardiac output in myocardial stress testing.

Dopexamine: Dopexamine is a synthetic dopamine analogue which is an agonist at β₂– and DA₁-receptors. It is also a weak DA₂-agonist and it inhibits the neuronal re-uptake of noradrenaline (uptake₁), but has no direct effects at β₁– or α-receptors. Its principal effect is β₂-agonism, producing vasodilatation in skeletal muscle; it is less potent at DA₁-receptors, but a more potent β₂-agonist than dopamine. It produces mild increases in heart rate, contractility and cardiac output (effects on β₂-receptors and noradrenaline uptake), renal and mesenteric vasodilatation (β₂ and DA₁ effects), and natriuresis (DA₁ effect). Coronary and cerebral blood flows are also increased. Systemic vascular resistance decreases and arterial pressure may decrease if intravascular volume is not maintained. Dopexamine has theoretical advantages in maintaining cardiac output and splanchnic blood flow in patients with systemic sepsis or heart failure. It is also used for this purpose in patients undergoing major abdominal surgery. Dopexamine also has anti-inflammatory effects (in common with other β-agonists) which are independent of its effects on gut mucosal perfusion. It is metabolized by hepatic methylation and conjugation and is eliminated mostly via the kidneys.

Fenoldopam is a dopamine (DA₁) agonist available in the USA which causes peripheral vasodilatation and increases renal blood flow and sodium and water excretion. It has been used in the treatment of hypertensive emergencies. Unlike some other vasodilators (e.g. sodium nitroprusside) it does not cause rebound hypertension after stopping the infusion.

Ephedrine: Ephedrine is a naturally occurring sympathomimetic amine which is now produced synthetically. It acts directly and indirectly as an agonist at α-, β₁– and β₂-receptors. The indirect actions are increased endogenous noradrenaline release and inhibition of MAO. Its cardiovascular effects are similar to those of adrenaline, but the duration of action is up to 10 times longer. It causes increases in heart rate, contractility, cardiac output and arterial pressure (systolic >  diastolic). It may predispose to arrhythmias. Systemic vascular resistance is usually unchanged because α-mediated vasoconstriction in some vascular beds is balanced by β-mediated vasodilatation in others, but renal and splanchnic blood flows decrease. It relaxes bronchial and other smooth muscle, and is occasionally used as a bronchodilator. It is active orally because it is not metabolized by MAO in the gut, and is useful by intramuscular injection because muscle blood flow is preserved. Ephedrine undergoes hepatic deamination and conjugation but significant amounts are excreted unchanged in urine. This accounts for its long duration of action and elimination half-life (3–6 h). Tachyphylaxis (a decreased response to repeated doses of the drug) occurs because of persistent occupation of adrenergic receptors and depletion of noradrenaline stores.

Ephedrine is often used to prevent or treat hypotension resulting from sympathetic blockade during regional anaesthesia or from the effects of general anaesthesia. Although widely used to prevent hypotension during regional anaesthesia in obstetric patients, it has largely been superseded for this indication by an infusion of phenylephrine, which has better effects on maternal and fetal haemodynamics. Oral or topical ephedrine is also useful as a nasal decongestant.

Phenylephrine: Phenylephrine is a potent synthetic direct-acting α₁-agonist, which has minimal agonist effects at α₂-and β-receptors. It has effects similar to those of noradrenaline, causing widespread vasoconstriction, increased arterial pressure, bradycardia (as a result of baroreflex activation) and a decrease in cardiac output. Venoconstriction predominates and diastolic pressure increases more than systolic pressure, so that coronary blood flow may increase. It is used as intermittent boluses (50-100 μg by slow injection) or an infusion (50–150 μg min^− 1) to maintain arterial pressure during general or regional anaesthesia, and also topically as a nasal decongestant and mydriatic. Absorption of phenylephrine from mucous membranes may occasionally produce systemic side-effects.

Methoxamine: Methoxamine is a direct-acting α₁-agonist which also has a weak β-antagonist action. It produces vasoconstriction, increased diastolic arterial pressure and decreases in cardiac output and heart rate from baroreflex activation and the mild β-blocking effect. It is no longer available in the UK.

Metaraminol: Metaraminol is a direct- and indirect-acting α- and β-agonist, which acts partly by being taken up into sympathetic nerve terminals and acting as a false transmitter for noradrenaline. Its α effects predominate, causing pronounced vasoconstriction; arterial pressure increases and a reflex bradycardia may occur.

Vasopressin: Arginine vasopressin (AVP) (formerly termed antidiuretic hormone) is a peptide hormone secreted by the hypothalamus. Its primary role is the regulation of body fluid balance. It is secreted in response to hypotension and promotes retention of water by action on specific cAMP-coupled V₂-receptors. It causes vasoconstriction by stimulating V₁-receptors in vascular smooth muscle and is particularly potent in hypotensive patients. It is increasingly used in the treatment of refractory vasodilatory shock which is resistant to catecholamines, although it can cause peripheral or splanchnic ischaemia. The vasopressin analogue desmopressin is used to treat diabetes insipidus. Another analogue, terlipressin, is used to limit bleeding from oesophageal varices in patients with portal hypertension as an adjunct to definitive treatment.

Phosphodiesterase Inhibitors: Phosphodiesterase inhibitors increase intracellular cAMP concentrations by inhibition of the enzyme responsible for cAMP breakdown (Fig. 8.4). Increased intracellular cAMP concentrations promote the activation of protein kinases, which lead to an increase in intracellular Ca^2 +. In cardiac muscle cells, this causes a positive inotropic effect and also facilitates diastolic relaxation and cardiac filling (termed ‘positive lusitropy’). In vascular smooth muscle, increased cAMP decreases intracellular Ca^2 + and causes marked vasodilatation. Several subtypes of phosphodiesterase (PDE) isoenzyme exist in different tissues. Theophylline is a non-specific PDE inhibitor, but the newer drugs (e.g. enoximone and milrinone) are selective for the PDE type III isoenzyme present in the myocardium, vascular smooth muscle and platelets. PDE III inhibitors are positive inotropes and potent arterial, coronary and venodilators. They decrease preload, afterload, pulmonary vascular resistance and pulmonary capillary wedge pressure (PCWP), and increase cardiac index. Heart rate may increase or remain unchanged. In contrast to sympathomimetics, they improve myocardial function without increasing oxygen demand or causing tachyphylaxis. Their effects are augmented by the co-administration of β₁-agonists (i.e. increases in cAMP production are synergistic with decreased cAMP breakdown). They have particular advantages in patients with chronic heart failure, in whom downregulation of myocardial β-adrenergic receptors occurs, so that there is a decreased inotropic response to β-sympathomimetic drugs. A similar phenomenon occurs with advanced age, prolonged (> 72 h) catecholamine therapy and possibly with surgical stress.

PDE III inhibitors are indicated for acute refractory heart failure, e.g. cardiogenic shock, or pre- or postcardiac surgery. However, long-term oral treatment is associated with increased mortality in patients with congestive heart failure. All may cause hypotension, and tachyarrhythmias may occur. Other adverse effects include nausea, vomiting and fever. Their half-life is prolonged markedly in patients with heart or renal failure and they are commonly administered as an i.v. loading dose over 5 min with or without a subsequent i.v. infusion. Milrinone is a bipyridine derivative whereas enoximone is an imidazole derivative. Enoximone undergoes substantial first-pass metabolism, and is rapidly metabolized to an active sulphoxide metabolite which is excreted via the kidneys and which may accumulate in renal failure. The elimination t_½ of enoximone is 1–2 h in healthy individuals but up to 20 h in patients with heart failure.

Glucagon: Glucagon is a polypeptide secreted by the α cells of the pancreatic islets. Its physiological actions include stimulation of hepatic gluconeogenesis in response to hypoglycaemia, amino acids and as part of the stress response. These effects are mediated by increasing adenylate cyclase activity and intracellular cAMP, by a mechanism independent of the β-adrenergic receptor (Fig. 8.4). It increases cAMP in myocardial cells and so increases cardiac contractility. Glucagon causes nausea and vomiting, hyperglycaemia and hyperkalaemia and is not used as an inotrope except in the management of β-blocker poisoning.

Calcium: Calcium ions are involved in cellular excitation, excitation-contraction coupling and muscle contraction in cardiac, skeletal and smooth muscle cells. Increased extracellular Ca^2 + increases intracellular Ca^2 + concentrations and consequently the force of contraction of cardiac myocytes and vascular smooth muscle cells. Massive blood loss and replacement with large volumes of calcium-free fluids or citrated blood (which chelates Ca^2 +) may cause a decrease in serum Ca^2 + concentration, especially in the critically ill. Therefore, Ca^2 + salts (e.g. calcium chloride or gluconate) may be administered, particularly during and after cardiopulmonary bypass. Intravenous calcium 5 mg kg^–1 may increase mean arterial pressure, but the effects on cardiac output and systemic vascular resistance are variable and there is little good evidence for the efficacy of Ca^2 + salts. Moreover, high Ca^2 + concentrations may cause cardiac arrhythmias and vasoconstriction, may be cytotoxic and may worsen the cellular effects of ischaemia. Calcium salts may be indicated for the treatment of hypocalcaemia (ionized Ca^2 + < 0.8 mmol L^–1), hyperkalaemia and calcium channel blocker toxicity.

Calcium Sensitizers: Levosimendan and pimobendan are positive inotropic drugs which act by stabilizing the troponin molecule in cardiac myocytes (by a cAMP- independent mechanism) and so increase myocyte Ca^2 + sensitivity without increasing Ca^2 + influx. Contractility is increased without an increase in oxygen consumption or a tendency to arrhythmias. Levosimendan also causes vasodilatation by opening K⁺ channels via an ATP-dependent mechanism and may be used as a second line agent in acute heart failure. It is available in Europe and South America. Pimobendan also inhibits phosphodiesterase-III and has been investigated for use in chronic heart failure. It is available in Japan.

Salbutamol: Salbutamol is the β₂-agonist used most commonly for the prevention and treatment of bronchospasm. When administered by metered dose inhaler (1 or 2 puffs, each delivering 100 μg), it acts within a few minutes, with a peak action at 30–60 min. In severe cases, it may be given by nebulizer (2.5–5.0 mg), repeated if required, or intravenously (either 250 μg by slow i.v. injection or as an infusion starting at 5 μg min^–1 and titrated to response). It is metabolized in the liver and excreted in urine both as metabolites and as unchanged drug; the proportions are dependent on the route of administration.

Ganglion Blocking Drugs: Nicotinic receptor antagonists (e.g. hexamethonium, pentolinium, trimetaphan) competitively inhibit the effects of ACh at autonomic ganglia and block both parasympathetic and sympathetic transmission. Sympathetic blockade produces venodilatation, decreased myocardial contractility and hypotension, but the effects vary depending on pre-existing sympathetic tone. Tachyphylaxis develops rapidly and these drugs have now been superseded.

Adrenergic Neurone Blocking Drugs: Guanethidine decreases peripheral sympathetic nervous system activity by competitively binding to noradrenaline binding sites in storage vesicles in the cytoplasm of postganglionic sympathetic nerve terminals. Further uptake of noradrenaline into the vesicles is inhibited and it is metabolized by cytoplasmic MAO, so the nerve terminals become depleted of noradrenaline. Guanethidine has local anaesthetic properties and does not cross the blood–brain barrier. It is sometimes used to produce intravenous regional sympathetic blockade in the treatment of chronic limb pain associated with excessive autonomic activity (reflex sympathetic dystrophy or complex regional pain syndromes). Bretylium has a similar mode of action; it is used in the treatment of resistant ventricular arrhythmias (see below).

α-Adrenergic Receptor Antagonists: α-Adrenergic antagonists (α-blockers) selectively inhibit the action of catecholamines at α-adrenergic receptors. They are used mainly as vasodilators for the second-line treatment of hypertension or as urinary tract smooth muscle relaxants in patients with benign prostatic hyperplasia. They also have an important role in the preoperative management of phaeochromocytoma (see Ch 37).

α-Blockers diminish vasoconstrictor tone, causing venous pooling and a decrease in peripheral vascular resistance. In common with other vasodilators, they may have indirect positive inotropic actions as a result of reductions in afterload and preload, so cardiac output may increase. They may be classified according to their relative selectivity for α₁– and α₂-receptors. Non-selective α-blockers commonly induce postural hypotension and reflex tachycardia, partly because α₂-blockade prevents the feedback inhibition of noradrenaline on its own release at presynaptic α₂-receptors, and neuronal noradrenaline concentrations increase. The action of noradrenaline at cardiac β-receptors then limits the hypotensive effects of non-selective α-blockers. In addition, the proportions of pre- and postsynaptic α₂-receptors in the arterial and venous smooth muscle may differ, so that α₁-selective drugs have a more balanced effect on venous and arterial circulations. The co-administration of a β-blocker may attenuate reflex tachycardia and produces a synergistic effect on arterial pressure.

α₁-Selective Antagonists: Selective α₁-blockers include prazosin, doxazosin, indoramin, and urapidil. Doxazosin has largely succeeded prazosin as it has a more prolonged duration of action. Reflex tachycardia and postural hypotension are less common than with direct-acting vasodilators (e.g. hydralazine) and the non-selective α-blockers, but may still occur on initiating therapy. Nasal congestion, sedation and inhibition of ejaculation may occur.

Labetalol (see below) is a competitive α₁-, β₁– and β₂-antagonist, which is more active at β- than at α-receptors. At low doses (5–10 mg i.v.), it decreases arterial pressure without producing a tachycardia. At higher doses, the β effect becomes more prominent, with negative inotropic and chronotropic effects. Carvedilol is an α₁– and β-receptor antagonist which also has direct vasodilator effects (see below).

α₂-Selective Antagonists: Drugs of this type, e.g. yohimbine, are not used because of the unacceptable incidence of adverse effects.

Non-Selective α-Antagonists: Non-selective α-blockers, e.g. phentolamine and phenoxybenzamine, produce more postural hypotension, reflex tachycardia and adverse gastrointestinal effects (e.g. abdominal cramps, diarrhoea) than α₁-selective drugs. Phentolamine 2–5 mg i.v. produces a rapid decrease in arterial pressure lasting 10–15 min and is used for the treatment of hypertensive crises.

Phenoxybenzamine binds covalently (i.e. irreversibly and non-competitively) to α-receptors so that its effects last up to several days, and may be cumulative on repeated dosing. It also reduces central sympathetic activity, which enhances vasodilatation, and has antagonist effects at 5-HT receptors. It is used for the preoperative preparation of patients with phaeochromocytoma (see Ch 37).

 their relative affinity for β₁– or β₂-receptors

 agonist/antagonist activity

 membrane-stabilizing effect

 ancillary effects (e.g. action at other receptors).

β₁– or β₂-Adrenergic Receptor Affinity: The relative potency of β-blockers is less important than their relative effects on the different β-receptor subtypes. Compounds are available which block preferentially either β₁– or β₂-receptors, although in clinical practice the β₁-selective drugs are more important. The first generation of β-blockers (e.g. propranolol, timolol) were non-selective; second-generation drugs (e.g. atenolol, metoprolol, bisoprolol) are selective for β₁-receptors but have no ancillary effects. The third generation of β-blockers are β₁-selective, but also have effects on other receptors (e.g. labetalol and carvedilol are antagonists at α₁-adrenergic receptors, and celiprolol produces vasodilatation by a mechanism involving endothelial nitric oxide). β₁-Selective (or ‘cardioselective’) drugs have theoretical advantages because some of the adverse effects of β-blockers are related to β₂-antagonism, but the selectivity of both drugs and tissues is only relative: all β₁-selective drugs antagonize β₂-receptors at higher doses, and 25% of cardiac β-receptors are of the β₂ subtype. However β₁-selective drugs appear to have fewer adverse effects on blood glucose control in diabetics, less effect on serum lipids and less effect on bronchial tone in patients with chronic obstructive pulmonary disease.

Partial Agonist Activity: Some β-blockers have intrinsic sympathomimetic activity (ISA), i.e. they are partial agonists. This stimulant effect is apparent at low levels of sympathetic activity, but at high levels of sympathetic discharge, blockade of endogenously released catecholamines is the major clinical effect. Partial agonists may be advantageous in patients with a low resting heart rate because they reduce the risk of AV conduction disturbance, and have theoretical advantages in patients with peripheral vascular disease or hyperlipidaemia. However, only β-blockers without partial agonist activity have been shown to be beneficial after myocardial infarction.

Membrane-Stabilizing Effect: Some β-blockers have a quinidine-like action, inhibiting Na⁺ transport in nerve and cardiac conducting tissue (‘membrane-stabilizing effect’). This may be demonstrated in vivo as a stabilizing effect on the cardiac action potential, reducing the slope of phase 4 noticeably, thus decreasing excitability and automaticity of the myocardium (see below). However, the membrane-stabilizing activity probably has little clinical significance because it occurs only at plasma concentrations above the therapeutic range, and the antiarrhythmic effect of β-blockade occurs via inhibition of the effects of catecholamines.

Ancillary Effects: Some of the newer β-blockers drugs have additional effects, e.g. action at α-receptors, vasodilatation, antioxidant effects and other actions. The relevance of these properties is discussed below.

Pharmacological Properties of β-Blockers: The pharmacological properties of β-blockers are summarized in Table 8.4. All are weak bases and most are well absorbed to produce peak plasma concentrations 1–3 h after oral administration. The more lipid-soluble drugs are almost completely absorbed, but are metabolized to a greater extent and tend to have a marked first-pass effect through the liver. This reduces their bioavailability, but is offset by the fact that the 4-hydroxylated metabolites so formed are also active. These active metabolites are excreted via the kidneys and may accumulate in patients with renal failure. Propranolol decreases both the clearance of amide local anaesthetics (by decreasing hepatic blood flow and inhibiting metabolism) and the pulmonary first-pass uptake of fentanyl. The first-pass metabolic pathways may also become saturated, so that proportionately higher plasma concentrations of the parent drug occur at higher oral doses. The first-pass effect is also a source of wide interindividual variation in plasma concentrations achieved from the same dose of primarily metabolized drugs, although β-blockers have a flat dose-response curve and large changes in plasma concentration may give rise to only a small change in degree of β-blockade. However, differences in individual plasma concentration–response relationships may occur, possibly as a result of variations in sympathetic tone or the formation of active metabolites. All β-blockers are distributed widely throughout the body and significant concentrations occur in the CNS, particularly for the more lipid-soluble drugs (e.g. propranolol).

The less lipid-soluble drugs (e.g. atenolol) are less well absorbed, are metabolized to a lesser extent, are excreted via the kidneys and tend to have longer half-lives. Atenolol, nadolol and sotalol are excreted largely unchanged in urine and so are little affected by impairment of liver function.

Indications for β-Blockade: See Tables 8.5 and 8.6 for indications for β-blockade.

Hypertension. β-Blockers have been regarded as first-line therapy for the treatment of hypertension for many years, either alone or in combination with other drugs. They are of proven benefit in reducing the incidence of stroke and the morbidity and mortality from coronary artery disease in younger hypertensive patients, although the effectiveness of β-blockade in patients aged > 60 years has been questioned recently. The antihypertensive effect results from a combination of factors.

Arterial pressure reduction begins within an hour of β-blocker administration, but several days may elapse before the plateau is reached and the full hypotensive effect of oral β-blockers takes about 2 weeks. This suggests the involvement of several mechanisms including readjustment of central and peripheral cardiovascular reflexes. During chronic administration, the hypotensive effects of β-blockers last longer than the pharmacological half-life, so that single daily dosage is adequate therapeutically. However, upregulation of receptors may occur, leading to adverse effects (tachycardia, hypertension, myocardial ischaemia) on abrupt withdrawal of β-blockers. This is important in surgical patients, and patients receiving long-term β-blockade should continue therapy throughout the perioperative period. There is some evidence that perioperative β-blockade reduces cardiac complications in high-risk patients undergoing major vascular surgery, but the data are conflicting. All β-blockers are equally effective as hypotensive drugs; patients unresponsive to one β-blocker are generally unresponsive to all.

Ischaemic heart disease. β-Blockers improve symptoms and decrease the frequency and severity of silent myocardial ischaemia in patients with ischaemic heart disease. The incidence of myocardial ischaemia in high-risk patients is reduced by perioperative β-blockade and long-term outcome may be improved. β-Blockers reduce heart rate and contractility, with consequent decreases in wall tension and myocardial oxygen demand. A slower heart rate also permits longer diastolic filling time and hence potentially greater coronary perfusion. The perfusion of ischaemic regions may be improved by redistribution of myocardial blood flow, and other additional mechanisms may be involved.

β-Blockade also reduces exercise-induced increases in arterial pressure, velocity of cardiac contraction and oxygen consumption at any workload. Partial agonists have less effect on the resting heart rate and theoretically increase the metabolic demand of the myocardium; they may be less effective in patients with angina at rest or at very low levels of exercise. In contrast to effects on arterial pressure, there is a more direct relationship between plasma concentration and antianginal effect. To achieve effective plasma concentrations over a sustained period as a single daily dosage, either the long half-life drugs (e.g. atenolol, nadolol) or slow-release preparations (e.g. oxprenolol-SR, propranolol-LA, metoprolol-SR) are required.

Secondary prevention of myocardial infarction. Early i.v. administration after acute myocardial infarction can decrease infarct size, the incidence of ventricular and supraventricular arrhythmias and mortality in both lower- and higher-risk groups (e.g. elderly patients or those with left ventricular dysfunction). Mortality is reduced by 20–40%, and the risk of re-infarction is reduced if oral therapy is continued for 2–3 years.

Obstructive cardiomyopathy. β-Blockers improve exercise tolerance and alleviate symptoms in hypertrophic obstructive cardiomyopathy by decreasing heart rate, myocardial work, contractility and, thus, outflow tract obstruction. However, the incidence of sudden death in this condition is not affected. The incidence of cyanotic episodes caused by pulmonary outflow obstruction in patients with Fallot’s tetralogy is reduced by a similar mechanism.

Congestive heart failure. Congestive heart failure is accompanied by a compensatory increase in sympathetic nervous stimulation with increased plasma and cardiac noradrenaline concentrations, leading to increases in cardiac output, systemic vascular resistance and afterload. Plasma renin concentration also increases. Although beneficial as an acute response in the short term, high circulating catecholamine concentrations are directly toxic to the myocardium. Desensitization of myocardial β₁-adrenergic receptors occurs via downregulation and altered signal transduction. In combination with chronically increased peripheral resistance, this leads to ventricular remodelling with progressively worsening myocardial function and a propensity to arrhythmias. Some second- and third-generation β-blockers (bisoprolol, metoprolol and carvedilol) have been shown to decrease morbidity and mortality in heart failure by improving ventricular function. The mechanism is primarily by upregulation of β-receptor density or function, although other factors may contribute, including slowing of heart rate or an antiarrhythmic effect. Bisoprolol and metoprolol are β₁-selective antagonists but carvedilol also has β₂– and α₁-antagonist and antioxidant effects which may contribute to its action. They must be introduced cautiously in heart failure because symptoms may initially worsen, and ventricular function improves only after 1 month of therapy.

Arrhythmias (see below). β-Blockers are effective in the treatment of arrhythmias caused by sympathetic nervous overactivity or after myocardial infarction. The mechanisms are related to β-blockade itself rather than any membrane-stabilizing effect, e.g. antagonism of catecholamine effects on the cardiac action potential and muscle contractility. The result is a slowing of rate of discharge from the sinus and any ectopic pacemaker, and slowing of conduction and increased refractoriness of the AV node. β-Blockers also slow conduction in anomalous pathways. They may be used i.v. to terminate an attack of supraventricular tachycardia or decrease the ventricular rate in atrial fibrillation and flutter; conversion to sinus rhythm may also be achieved. If given within 30 min of i.v. verapamil, there is a danger of severe bradycardia or asystole. Most β-blockers have similar antiarrhythmic effects in adequate dosage, but esmolol has the advantage of a short half-life (see below) so that adverse effects are limited. They are also useful as second-line alternatives for the treatment of ventricular tachycardia. Sotalol has both class 2 and class 3 antiarrhythmic activity (see below) and is licensed for use only for its antiarrhythmic action, in particular for the treatment of supraventricular and ventricular tachycardias.

Miscellaneous. β-Blockers are prescribed for migraine prophylaxis, essential tremor and anxiety states. They are useful for glaucoma because they decrease intraocular pressure, probably by reducing the production of aqueous humour. Topical preparations (e.g. timolol, betaxolol, carteolol) are used in an attempt to decrease adverse effects but significant systemic absorption may still take place; bradycardia, hypotension and bronchospasm may occur, particularly during anaesthesia. β-Blockers diminish the symptoms of thyrotoxicosis and are used as part of preoperative preparation before thyroidectomy. They may be used also as part of a hypotensive anaesthetic technique.

Adverse Reactions to β-Blockers: All available β-blockers have similar adverse effects, although their magnitude depends on β₁-selectivity and the presence or absence of partial agonist activity. The reactions may be classified as follows.

Reactions Resulting from β-Blockade:

Other: Increased muscle fatigue can occur, possibly resulting from blockade of β₂-mediated vasodilatation in muscles during exercise. A withdrawal phenomenon may occur after abrupt cessation of long-term therapy for angina, causing rebound tachycardia, worsening angina or precipitation of myocardial infarction. Impotence occurs commonly during chronic β-blocker therapy.

Idiosyncratic Reactions: Central nervous system effects occur with some β-blockers, including nightmares, hallucinations, insomnia and depression. These effects are more common with the lipophilic drugs (e.g. propranolol, acebutolol, oxprenolol and metoprolol). Gastrointestinal reactions include nausea, vomiting and diarrhoea.

Newer β-Blockers: Recently introduced third- generation β-blockers (e.g. labetalol, celiprolol, nevibolol and carvedilol) are mostly non-selective (β₁ > β₂) antagonists which also produce vasodilatation by several mechanisms. Labetalol and carvedilol are also α₁-antagonists; bucindolol produces direct vasodilatation by a cAMP-dependent mechanism. The severity of some of the adverse effects of β-blockade may be less with those drugs with vasodilating properties.

Labetalol is a competitive α₁-, β₁– and β₂-antagonist, which is a partial agonist at β₂-receptors. It is four to seven times more potent at β- than at α-receptors and is useful for the prevention and treatment of perioperative hypertension, or to produce controlled hypotension (see Ch 21). It is also available as an oral preparation for the treatment of chronic hypertension or the preoperative management of phaeochromocytoma (see Ch 37). Intravenous labetalol in small increments (e.g. 5–10 mg) produces a controlled decrease in arterial pressure over 5–10 min with no change in cardiac output or reflex tachycardia, suggesting that at this dose the vasodilating action predominates. At higher doses, the β-effect becomes more prominent, with negative inotropic and chronotropic effects.

Carvedilol is an antagonist at α₁– and β-receptors (with relative β:α₁ selectivity of 10:1 and no partial agonist activity), but it has other effects including significant antioxidant activity, inhibition of endothelin synthesis and possibly calcium channel blockade in higher doses; these may account for some of its beneficial activity in patients with heart failure. Carvedilol is a stereoisomer which undergoes extensive first-pass metabolism with the production of active metabolites.

Nebivolol is a lipophilic β₁-selective blocker which is administered as a racemic mixture of equal proportions of D– and L-enantiomers. It has no membrane-stabilizing activity but has vasodilatory effects probably mediated by endothelial nitric oxide.

Celiprolol is a β₁-selective blocker which is a weak β₂-agonist and has α₂-antagonist activity. It also has direct vasodilator effects which may be mediated by endothelial nitric oxide release. Celiprolol is excreted unchanged.

Esmolol is a rapid-onset, short-acting β₁-selective blocker with no membrane-stabilizing or partial agonist activity and is only available for i.v. use. It has an onset time of 1–2 min and is metabolized rapidly by red cell esterases (distinct from plasma cholinesterases); its elimination half-life is 9 min. The rapid onset and offset of effect are an advantage in the perioperative period because any effects such as bradycardia or hypotension are short-lived. It is effective in preventing or controlling intraoperative tachycardia and hypertension, and is also useful for the treatment of supraventricular tachyarrhythmias, e.g. atrial fibrillation or flutter. It may be given as a slow i.v. bolus of 0.5–2.0 mg kg^–1 or an infusion of 25–500 μg kg^–1 min^–1; its effects terminate within 10–20 min of stopping the infusion.

Clinical Applications of ACE Inhibitors: ACE inhibitors are established in the treatment of hypertension and congestive heart failure. They improve left ventricular dysfunction after myocardial infarction, delay the progression of diabetic nephropathy and have a protective effect in non-diabetic chronic renal failure. ACE inhibitors improve vascular endothelial function by their effects on AT-II and bradykinin, and improve long-term cardiovascular outcome in patients with established vascular disease. ACE inhibitors have a common mechanism of action, differing in the chemical structure of their active moieties in potency, bioavailability, plasma half-life, route of elimination, distribution and affinity for tissue-bound ACE (Table 8.10). Most of the newer compounds are prodrugs, converted to an active metabolite by the liver, and have a prolonged duration of action. Most are excreted via the kidneys, and dosage should be reduced in the elderly and those with impaired renal or cardiac function. Enalapril is also available as the active drug, enalaprilat, and may be administered i.v. for the treatment of hypertensive emergencies.

ACE inhibitors are generally well tolerated, with no rebound hypertension after stopping therapy and few metabolic effects. Symptomatic first-dose hypotension may occur, particularly in hypovolaemic or sodium-depleted patients with high plasma renin concentrations. Symptomatic hypotension was more common with the higher doses originally used. ACE inhibitors have a synergistic effect with diuretics (which increase the activity of the renin-angiotensin system) but are less effective in patients taking NSAIDs.

Adverse effects of ACE inhibitors are classified into those that are class-specific (related to inhibition of ACE) and those which relate to specific drugs. Class-specific effects include hypotension, renal insufficiency, hyperkalaemia, cough (10%) and angioneurotic oedema (0.1–0.2%). ACE inhibitors may cause renal impairment, particularly if renal perfusion is decreased (e.g. because of renal artery stenosis, congestive heart failure or hypovolaemia) or if there is pre-existing renal disease. Renal impairment is also more likely in the elderly or those receiving NSAIDs, and renal function should be checked before starting ACE inhibitor therapy, and monitored subsequently. Hyperkalaemia (plasma K⁺ concentration usually increases by 0.1–0.2 mmol L^–1 because of decreased aldosterone concentrations) may be more marked in those with impaired renal function or in patients taking potassium supplements or potassium-sparing diuretics. The mechanism of cough is not known but is mediated by C fibres and may be related to bradykinin or substance P production. It is reversible on stopping the ACE inhibitor. Other adverse effects include upper respiratory congestion, rhinorrhoea, gastrointestinal disturbances, and increased insulin sensitivity and hyperglycaemia in diabetic patients.

Some adverse effects, e.g. skin rashes (1%), taste disturbances, proteinuria (1%) and neutropenia (0.05%), are related to the presence of a sulphydryl group (e.g. captopril). ACE inhibitors are contraindicated in pregnancy.

Although anaesthesia per se has no direct effect on the RAS or ACE inhibitors, the RAS is activated by several stimuli which may occur during the perioperative period. These include blood or fluid losses and the stress response to surgical stimulation. RAS activation contributes to the maintenance of arterial pressure after haemorrhage, or during anaesthesia. Refractory hypotension during anaesthesia has been reported in patients receiving long-term antihypertensive treatment with ACE inhibitors, and it has been recommended that they are stopped 24 h before surgery if significant blood loss or fluid shifts are likely. ACE inhibitors improve ventricular function in patients with heart failure or after myocardial infarction but it is not known whether acute cessation before surgery is harmful. Conversely, they may have beneficial effects on regional blood flow and have been associated with improved renal function in patients undergoing aortic surgery.

 increased automaticity

 re-entry phenomena

 pathological afterdepolarizations.

Class 1a: These drugs (see Tables 8.14 and 8.15) are used for the treatment and prevention of ventricular and supraventricular arrhythmias. Their use in the prevention of atrial fibrillation has declined because of proarrhythmic effects causing increased mortality, especially in patients with ischaemic heart disease or poor LV function. They may induce torsades de pointes (a form of polymorphic ventricular tachycardia) even in patients without structural heart disease.

Quinidine is an isomer of quinine with antimuscarinic and α-blocking properties. It was formerly used in the treatment of atrial and supraventricular tachycardias. Disopyramide is useful in supraventricular tachycardias and as a second-line agent to lidocaine in ventricular arrhythmias. It has less action on the His–Purkinje system than quinidine, but greater antimuscarinic and negative inotropic effects.

Procainamide has similar effects to quinidine and may cause hypotension after i.v. administration. It may be used i.v. to terminate ventricular arrhythmias or as an oral antiarrhythmic, although it has a short half-life and requires frequent administration or the use of a sustained-release oral preparation.

Ajmalin is a quinidine-like drug used for the treatment of Wolff–Parkinson–White (WPW) syndrome. It inhibits intraventricular conduction and prolongs AV conduction time, and is available in Europe.

Class 1b: Class 1b drugs are useful for the prevention and treatment of premature ventricular contractions, ventricular tachycardia and ventricular fibrillation, particularly associated with ischaemia.

Lidocaine is the first-choice drug for ventricular arrhythmias resistant to DC cardioversion. It decreases normal and abnormal automaticity and decreases action potential and refractory period durations. The threshold for ventricular fibrillation is raised but it has minimal haemodynamic effects. The antiarrhythmic properties of lidocaine are enhanced by hypoxaemia, acidosis and hyperkalaemia, so that it is particularly effective in ischaemic cells, e.g. after acute myocardial infarction, during cardiac surgery or in arrhythmias associated with digitalis toxicity. Lidocaine may cause CNS toxicity. Cardiotoxic effects (hypotension, bradycardia or heart block) occur at higher doses and are potentiated by hypoxaemia, acidosis and hypercapnia. Clearance is decreased if hepatic blood flow is decreased (e.g. in the elderly, those with congestive heart failure, after myocardial infarction), and also by β-blockers, cimetidine and liver disease. In these circumstances, the dose should be reduced by 50%. It is less effective in the presence of hypokalaemia.

Mexiletine is a lidocaine analogue which is well absorbed orally with high bioavailability. Adverse effects are similar to those of lidocaine; nausea and vomiting are also common during oral treatment.

Class 1c: Class 1c drugs are used for the prevention and treatment of supraventricular and ventricular tachyarrhythmias and junctional tachycardias with or without an accessory pathway. They are proarrhythmogenic, particularly in patients with myocardial ischaemia, poor left ventricular function or after myocardial infarction, and although effective in chronic atrial fibrillation, they are reserved for life-threatening arrhythmias.

Flecainide is a procainamide derivative with little effect on repolarization, the refractory period or AP duration, but unlike other drugs in this class, it decreases automaticity and produces dose-dependent widening of the QRS complex. In acute atrial fibrillation, intravenous flecainide usually restores sinus rhythm and is useful prophylaxis against further episodes of atrial fibrillation. However, it increases the risk of ventricular arrhythmias after myocardial infarction, especially in patients with structural cardiac disease.

Propafenone has a complex pharmacology including weak antimuscarinic, β-adrenergic receptor and calcium channel blocking effects. It should be used with caution in patients with reactive airways disease. Interaction with digoxin may increase plasma digoxin concentrations.