Drugs Acting on the Cardiovascular System

Many drugs have either primary or secondary effects on the cardiovascular and autonomic nervous systems. Several of the drugs discussed in this chapter have more than one clinical indication and the drugs are considered according to their mechanism of action. An understanding of drugs acting on the cardiovascular and autonomic nervous systems requires an understanding of autonomic physiology and pharmacology.

THE AUTONOMIC NERVOUS SYSTEM

The term autonomic nervous system (ANS) refers to the nervous and humoral mechanisms which modify the function of the autonomous or automatic organs. These include heart rate and force of contraction, calibre of blood vessels, contraction and relaxation of smooth muscle in gut, bladder and bronchi, visual accommodation and pupillary size. Other functions include regulation of secretion from exocrine and other glands and aspects of metabolism (e.g. glycogenolysis and lipolysis) (Table 8.1). There is constant activity of both the sympathetic and parasympathetic nervous systems even at rest. This is termed sympathetic or parasympathetic tone and allows alterations in autonomic activity to produce rapid two-way regulation of physiological effect. The ANS is controlled by centres in the spinal cord, brainstem and hypothalamus, which are in turn influenced by higher centres in the cerebral and particularly the limbic cortex. The ANS is also influenced by visceral reflexes whereby afferent signals enter the autonomic ganglia, spinal cord, hypothalamus or brainstem and directly elicit appropriate reflex responses via the visceral organs. The efferent autonomic signals are transmitted through the body to two major subdivisions (separated by anatomical, physiological and pharmacological criteria), the sympathetic and the parasympathetic nervous systems.

TABLE 8.1

Effects of the Sympathetic and Parasympathetic Nervous Systems on Peripheral Effector Organs, and Receptor Subtypes Mediating these Functions (Where Known)

^a Muscarinic receptors are present on vascular smooth muscle, but they are independent of parasympathetic innervation and have little or no physiological role in the control of vasomotor tone.

^b Sympathetic cholinergic fibres supply sweat glands and arterioles in some sites.

All postganglionic parasympathetic fibres are muscarinic (M), but in many sites the subtype has not been identified.

Parasympathetic Receptor Pharmacology

Parasympathetic receptors have been classified according to the actions of the alkaloids muscarine and nicotine. The actions of ACh at the postganglionic membrane are mimicked by muscarine and are termed muscarinic, whereas preganglionic transmission is termed nicotinic. ACh is also the neurotransmitter at the neuromuscular junction, via nicotinic receptor sites. Five subtypes of muscarinic receptors (M₁–M₅) have been characterized; all five subtypes exist in the CNS, but there are differences in their peripheral distribution and function (Table 8.2). M₁-receptors are found in the stomach, where they mediate acid secretion, and in inflammatory cells in the lung (including mast cells and eosinophils) where they may have a role in airway inflammation. M₂-receptors predominate in the myocardium, where they modulate heart rate and impulse conduction. Prejunctional M₂-receptors are also involved in the regulation of synaptic noradrenaline and postganglionic ACh release. M₃-receptors are present in classic postsynaptic sites in glandular tissue (of the GI and respiratory tract) and bronchial smooth muscle, where they mediate most of the post-junctional effects of ACh. M₄-receptors have been isolated in cardiac and lung tissue in animal models and may have inhibitory effects, but the distribution and functions of M₅-receptors are not yet defined. In common with adrenergic receptors, muscarinic receptors are coupled to membrane-bound G-proteins although the subtypes differ in the second messenger system with which they interact. Currently available anticholinergics probably act at all muscarinic receptor subtypes but their clinical spectra differ, which suggests that they may have differential effects at different subtypes.

TABLE 8.2

Properties of Muscarinic (M₁–M₅) Receptors

IP₃ stimulates inositol triphosphate production.

cAMP inhibits adenylate cyclase to decrease cAMP formation.

DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

Sympathomimetic Drugs

Sympathomimetic drugs partially or completely mimic the effects of sympathetic nerve stimulation or adrenal medullary discharge. They may act:

directly on the adrenergic receptor, e.g. the catecholamines, phenylephrine, methoxamine

indirectly causing release of noradrenaline from the adrenergic nerve ending, e.g. amphetamine

by both mechanisms, e.g. dopamine, ephedrine, metaraminol.

The drugs may be classified according to their structure (catecholamine/non-catecholamine), their origin (endogenous/synthetic) and their mechanism of action (via adrenergic receptors or via a non-adrenergic mechanism) (Table 8.3). Drugs which affect myocardial contractility are termed inotropes, although this term is usually applied to those drugs that increase cardiac contractility (strictly ‘positive inotropes’). Myocardial contractility may be increased by:

TABLE 8.3

Classification of Sympathomimetic Drugs

increasing intracellular cAMP by activation of the adenylate cyclase system (e.g. catecholamines and other drugs acting via the adrenergic receptor)

decreasing breakdown of cAMP (e.g. phosphodiesterase inhibitors)

increasing intracellular calcium availability (e.g. digoxin, calcium salts, glucagon)

increasing the response of contractile proteins to calcium (e.g. levosimendan) (Fig. 8.4).

FIGURE 8.4 Intracellular action of positive inotropic drugs. PDE; phosphodiesterase.

Inotropes may also be classified into positive inotropic drugs which also produce systemic vasoconstriction (‘inoconstrictors’) and those which also produce systemic vasodilatation (‘inodilators’). Inoconstrictors include noradrenaline, adrenaline and ephedrine. Inodilators are dobutamine, dopexamine, isoprenaline and phosphodiesterase inhibitors. Dopamine is an inodilator at low dose, and an inoconstrictor at higher doses.

Catecholamines

Catecholamine drugs may be endogenous (adrenaline, noradrenaline and dopamine) or synthetic (dobutamine, dopexamine and isoprenaline). Several other drugs with a non-catecholamine structure produce sympathomimetic effects via adrenergic receptors, e.g. ephedrine and phenylephrine. All catecholamine drugs are inactivated in the gut by MAO and are usually only administered parenterally. They all have very short half-lives in vivo, and so when given by intravenous infusion, their effects may be controlled by altering the infusion rate. The comparative effects of different inotropes and vasopressors are outlined below.

Endogenous Catecholamines

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.

Synthetic Catecholamines

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.

Non-Catecholamine Sympathomimetics

Synthetic sympathomimetic drugs may mimic the effect of adrenaline at adrenergic receptors (direct-acting) or may produce effects by causing release of endogenous noradrenaline from postganglionic sympathetic nerve terminals (indirect-acting). Some drugs have direct and indirect sympathomimetic effects (e.g. ephedrine, metaraminol). Direct-acting compounds may affect α- or β-receptors selectively, whereas indirect-acting compounds have predominantly α- and β₁-agonist effects (as noradrenaline is only a weak β₂-agonist). Indirect-acting compounds are taken up into the nerve terminal via the noradrenaline re-uptake pathway, and so their effect is reduced by drugs which block noradrenaline re-uptake (e.g. tricyclic antidepressants). Conversely, the effect of direct-acting drugs is enhanced. In patients treated with drugs which decrease sympathetic nervous system activity (e.g. clonidine, reserpine), the cardiovascular response to indirect-acting drugs is diminished; however, upregulation of adrenergic receptors occurs and an increased response to direct-acting sympathomimetics is seen. Drugs with selective α-adrenergic receptor effects (e.g. phenylephrine, methoxamine) are potent vasoconstrictors.

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.

Selective β₂-Agonists

Selective β₂-receptor agonists (e.g. salbutamol, terbutaline, formoterol and salmeterol) relax bronchial, uterine and vascular smooth muscle while having much less effect on the heart than isoprenaline. These drugs are partial agonists (their maximal effect at β₂-receptors is less than that of isoprenaline) and are only partially selective for β₂-receptors. They are used widely in the treatment of bronchospasm (see Ch 9). Although less cardiotoxic than isoprenaline, dose-related tremor, tachyarrhythmias, hyperglycaemia, hypokalaemia and hypomagnesaemia may occur. β₂-Agonists are resistant to metabolism by COMT and therefore have a prolonged duration of action (mostly 3–5 h). Salmeterol is highly lipophilic, has a strong affinity for the β₂-adrenergic receptor, is longer acting than the other β₂-agonists and so is used for maintenance therapy in chronic asthma in combination with inhaled steroids. β₂-Agonists are usually administered by the inhaled (metered dose inhaler or nebulizer) or intravenous routes because of unpredictable oral absorption and a high hepatic extraction ratio. When inhaled, only 10–20% of the administered dose reaches the lower airways; this proportion is reduced further when administered via a tracheal tube. Nevertheless, systemic absorption does occur, although adverse effects are less common during long-term therapy.

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.