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 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.
All postganglionic parasympathetic fibres are muscarinic (M), but in many sites the subtype has not been identified.
The sympathetic nervous system includes nerves which originate in the spinal cord between the first thoracic and second lumbar segments (T1 to L2). Fibres leave the spinal cord with the anterior nerve roots and then branch off as white rami communicantes to synapse in the bilateral paravertebral sympathetic ganglionic chains, although some preganglionic fibres synapse instead in the paravertebral ganglia (e.g. coeliac, mesenteric and hypogastric) in the abdomen before travelling to their effector organ with the relevant arteries. Postganglionic fibres travel from paravertebral ganglia in sympathetic nerves (to supply the internal viscera, including the heart) and spinal nerves (which innervate the peripheral vasculature and sweat glands). Sympathetic nerves throughout the circulation contain vasoconstrictor fibres, particularly in the kidneys, spleen, gut and skin; however, sympathetic vasodilator fibres predominate in skeletal muscle, and coronary and cerebral vessels. Sympathetic stimulation therefore causes predominantly vasoconstriction but also a redistribution of blood flow to skeletal muscle; constriction of venous capacitance vessels may decrease their volume and thereby increase venous return. The effects of sympathetic stimulation at different receptors and effector organs are summarized in Table 8.1. The distribution of sympathetic nerve fibres to an organ or region may differ from the sensory or motor supply, according to its embryonic origin. For example, sympathetic fibres to the heart arise from T1 to T5 (but predominantly from T1 to T4), the neck is supplied by fibres from T2, the chest by fibres from T3 to T6 and the abdomen by fibres from T7 to T11.
The neurotransmitter present in preganglionic neurones is acetylcholine (ACh). These and other neurones containing ACh are termed cholinergic. However, the activity of preganglionic neurones is modulated by several other neuropeptides including enkephalin, neurotensin, substance P, somatostatin, nitric oxide, serotonin and catecholamines. ACh is the transmitter at all preganglionic synapses, acting via nicotinic receptors. Postganglionic sympathetic neurones secrete noradrenaline and are termed adrenergic (except for postganglionic sympathetic nerve fibres to sweat glands, pilo-erector muscles and some blood vessels, which are cholinergic).
Activation of preganglionic nicotinic fibres to the adrenal medulla causes the release of adrenaline (adrenaline), which is released primarily as a circulating hormone and is only found in insignificant amounts in the nerve endings. Endogenous catecholamines (adrenaline, noradrenaline (norepinephrine) and dopamine) are synthesized from the essential amino acid phenylalanine. Their structure is based on a catechol ring (i.e. a benzene ring with -OH groups in the 3 and 4 positions), and an ethylamine side chain (Figs 8.1 and 8.2); substitutions in the side chain produce the different compounds. Dopamine may act as a precursor for both adrenaline and noradrenaline when administered exogenously (see below).
Most noradrenaline released from sympathetic nerves is taken back into the presynaptic nerve ending for storage and subsequent reuse. Re-uptake is by active transport back into the nerve terminal cytoplasm and then into cytoplasmic vesicles. This mechanism of presynaptic re-uptake, termed uptake1, is dependent on adenosine triphosphate (ATP) and Mg2 +, is enhanced by Li+ and may be blocked by cocaine and tricyclic antidepressants. Endogenous catecholamines entering the circulation by diffusion from sympathetic nerve endings or by release from the adrenal gland are metabolized rapidly by the enzymes monamine oxidase (MAO) and catechol O-methyltransferase (COMT) in the liver, kidneys, gut and many other tissues. The metabolites are conjugated before being excreted in urine as 3-methoxy-4-hydroxymandelic acid, metanephrine (from adrenaline) and normetanephrine (from noradrenaline) (Fig. 8.3). Noradrenaline taken up into the nerve terminal may also be deaminated by cytoplasmic MAO.
Another mechanism for the postsynaptic cellular re-uptake of catecholamines, termed uptake2, is present predominantly at the membrane of smooth muscle cells. It may be responsible for the termination of action of catecholamines released from the adrenal medulla.
The actions of catecholamines are mediated by specific postsynaptic cell surface receptors. The original classification of these receptors into α- and β-adrenergic receptors was based upon the effects of adrenaline at peripheral sympathetic sites, α-receptors being responsible for vasoconstriction and β-receptors mediating effects on the heart, and bronchial and intestinal smooth muscle. However, several subtypes of α- and β-receptors exist in addition to receptors specific for dopamine (DA1 and DA2 subtypes). Two α- and β-receptor subtypes are well defined on functional, anatomical and pharmacological grounds (α1 and α2, β1 and β2). A third β-receptor subtype, β3, is found in adipocytes, skeletal and ventricular muscle, and the vasculature. At least three further subtypes of both α1– and α2-receptors and five subtypes of DA-receptor have also been identified, although their precise functions are unclear. Differentiation of receptor subtypes is now based more directly on the effects of various catecholamine agonist compounds (including endogenous catecholamines). Noradrenaline and adrenaline are agonists at both α1– and α2-receptors; noradrenaline is slightly more potent at α1-receptors, and more potent at α2-receptors. Adrenaline has a more potent action at β1-receptors, and also acts at β2-receptors, whereas noradrenaline has no β2-effects.
Until recently, it was thought that β1-receptors predominated in the heart, mediating increases in force and rate of contraction, and β2-receptors existed in bronchial, uterine and vascular smooth muscle, mediating relaxation. In fact, most organs and tissues contain both β1– and β2-receptors, which may even serve the same function. For example, up to 25% of cardiac β-receptors in the normal individual are of the β2 subtype, and this proportion may be increased in patients with heart failure. It is now apparent that β1-receptors in tissues are situated on the postsynaptic membrane of adrenergic neurones and respond to released noradrenaline. β2-Receptors are presynaptic and, when stimulated (principally by circulating catecholamines), they modulate autonomic activity by promoting neuronal noradrenaline release. β3-Receptors mediate thermogenesis and lipolysis in adipocytes but antagonize the effects of β1– and β2-receptors on the heart, and also mediate vasodilatation. Similarly, α1-receptors are present on the postsynaptic membrane, whereas α2-receptors are predominantly presynaptic, responding to circulating adrenaline but also mediating feedback inhibition of sympathetic nerve activity. Central α2 stimulation causes decreases in arterial pressure, peripheral resistance, venous return, myocardial contractility, cardiac output and heart rate by inhibition of sympathetic outflow. Postsynaptic α2-receptors present on platelets and in the CNS mediate platelet aggregation and membrane hyperpolarization, respectively.
Postsynaptic dopamine receptors (DA1) are present in vascular smooth muscle of the renal, splanchnic, coronary and cerebral circulations, where they mediate vasodilatation. They are also situated on renal tubules, where they inhibit sodium reabsorption, causing natriuresis and diuresis. Postsynaptic DA2-receptors are widespread in the CNS and occur on the presynaptic membrane of sympathetic nerves and in the adrenal gland. Stimulation of presynaptic DA2-receptors inhibits dopamine release by negative feedback.
Postganglionic sympathetic fibres supplying sweat glands and arterioles in some areas of skin and skeletal muscle are cholinergic. Vascular smooth muscle also contains non-innervated cholinergic receptors which mediate vasodilatation in response to circulating agonists. Cholinergic effects on vascular smooth muscle are usually minimal but may be involved in the mechanism of vasovagal attacks.
Both α- and β-adrenergic receptors are proteins with a similar basic structure, comprising seven hydrophobic transmembrane domains and an intracellular chain. Differences in amino acid sequences of the intracellular chain differentiate α- and β-receptors. Both are linked to guanine nucleotide binding proteins (G-proteins) in the cell membrane which mediate the generation of second messengers that activate intracellular events. These second messenger systems include enzymes (adenylate cyclase, phospholipases) and ion channels (for calcium and potassium).
In addition to functional differences, α- and β-receptors differ in the intracellular mechanisms by which they act. Stimulation of β1– and β2-receptors activates Gs-proteins, which activate adenylate cyclase and cause the generation of intracellular cyclic adenosine monophosphate (cAMP). cAMP activates intracellular enzyme pathways (the third messengers) to produce the associated alteration in cell function (e.g. increased force of cardiac muscle contraction, liver glycogenolysis, bronchial smooth muscle relaxation). In cardiac myocytes, the intracellular pathway involves the activation of protein kinases to phosphorylate intracellular proteins and increase intracellular Ca2 + concentrations. Intracellular cAMP concentration is modulated by the enzyme phosphodiesterase, which breaks down cAMP to inactive 5′ AMP. This is the site of action of phosphodiesterase inhibitor drugs. The balance between production and degradation of cAMP is an important regulatory system for cell function. α2-Receptors interact with Gi-proteins to inhibit adenylate cyclase and Ca2 + channels, but activate K+ channels, phospholipase C and phospholipase A2. Cholinergic M2-receptors and somatostatin affect Gi-proteins in the same way.
In contrast, α1-receptor stimulation does not directly affect intracellular cAMP levels, but causes coupling with another G-protein, Gq, to activate membrane- bound phospholipase C. This in turn hydrolyses phosphatidylinositol biphosphate (PIP2) to inositol triphosphate (IP3), which produces changes in intracellular Ca2 + concentration and binding. These lead, for example, to smooth muscle contraction.
The parasympathetic nervous system controls vegetative functions, e.g. the digestion and absorption of nutrients, excretion of waste products and the conservation and restoration of energy. Parasympathetic neurones arise from cell bodies of the motor nuclei of cranial nerves III, VII, IX and X in the brainstem, and from the sacral segments of the spinal cord (‘the craniosacral outflow’). Preganglionic fibres run almost to the organ innervated and synapse in ganglia within the organ, giving rise to postganglionic fibres which then supply the relevant tissues. The ganglion cells may be well organized (e.g. the myenteric plexus of the intestine) or diffuse (e.g. in the bladder or vasculature). As the majority of all parasympathetic nerves are contained in branches of the vagus nerve, which innervates the viscera of the thorax and abdomen, increased parasympathetic activity is characterized by signs of vagal overactivity. Parasympathetic fibres also pass to the eye via the oculomotor (third cranial) nerve, and to the lacrimal, nasal and salivary glands via the facial (fifth) and glossopharyngeal (ninth) nerves. Fibres originating in the sacral portion of the spinal cord pass to the distal GI tract, bladder and reproductive organs. The effects of parasympathetic stimulation at different receptors and effector organs are summarized in Table 8.1
The chemical neurotransmitter at both pre- and postganglionic synapses is ACh, although transmission at postganglionic synapses may be modulated by other substances, including GABA, serotonin and opioid peptides. ACh is synthesized in the cytoplasm of cholinergic nerve terminals by the combination of choline and acetate (in the form of acetyl-CoA, which is synthesized in the mitochondria as a product of normal cellular metabolism). ACh is stored in specific agranular vesicles and released from the presynaptic terminal in response to neuronal depolarization to act at specific receptor sites on the postsynaptic membrane. It is rapidly metabolized by the enzyme acetylcholinesterase (AChE) to produce acetate and choline. Choline is then taken up into the presynaptic nerve ending for the regeneration of ACh. AChE is synthesized locally at cholinergic synapses, but is also present in erythrocytes and parts of the CNS. Butyryl cholinesterase (also termed plasma cholinesterase or pseudocholinesterase) is synthesized in the liver and is found in the plasma, skin, GI tract and parts of the CNS, but not at cholinergic synapses or the neuromuscular junction. It may metabolize ACh, in addition to some neuromuscular blockers (e.g. succinylcholine and mivacurium), but its physiological role probably involves the breakdown of other choline esters which may be present in the intestine.
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.
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:
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.
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.
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.
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 Ca2 +. 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 Ca2 + 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 t½ 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 Ca2 + increases intracellular Ca2 + 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 Ca2 +) may cause a decrease in serum Ca2 + concentration, especially in the critically ill. Therefore, Ca2 + 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 Ca2 + salts. Moreover, high Ca2 + 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 Ca2 + < 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 Ca2 + sensitivity without increasing Ca2 + 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-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.
Sympatholytic drugs antagonize the effects of the sympathetic nervous system either at central adrenergic neurones, peripheral autonomic ganglia or neurones, or at postsynaptic α- or β-receptors. Most are hypotensive drugs, although they have other effects and indications.
Centrally acting drugs act by stimulation of central α2-receptors to decrease sympathetic tone. They were used as antihypertensive drugs, but have been superseded for this purpose by newer drugs with fewer adverse effects. They are also agonists at central imidazoline (I1) receptors, which contributes to their hypotensive action. I1 receptors are present in several peripheral tissues, including the kidney. Central α2-stimulation causes decreases in arterial pressure, peripheral resistance, venous return, myocardial contractility, cardiac output and heart rate, but baroreceptor reflexes are preserved and the pressor response to ephedrine or phenylephrine may be exaggerated. Stimulation of peripheral α2-receptors on vascular smooth muscle causes direct arteriolar vasoconstriction, although the central effects of these drugs predominate overall. However, severe rebound hypertension may occur on stopping chronic oral therapy. α2-Receptors in the dorsal horn of the spinal cord modulate upward transmission of nociceptive signals by modifying local release of substance P and CGRP. Centrally acting α2