Part I Anaesthesia Refresher Course – 2018 University of Cape Town 06 Inotropes

Dr Frank Schneider

Dept of Anaesthesia & Perioperative Medicine University of Cape Town

An inotrope (derived from the Greek for turning or moving fibre), is the general term used to describe a substance which alters cardiac muscle contractility. Although inotropes can be positive or negative in their effect, this chapter will be limited to the discussion of positive inotropes and concentrate on their cardiovascular effect. A short review of definitions and basic pharmacology will hopefully help with understanding of mechanisms at a cellular level.

Definitions

Positive inotropes increase the force of contraction, but often also the rate of contraction or heart rate (chronotropy), ease of excitability of cardiac muscle (bathmotropy), velocity of conduction through cardiac tissue (dromotropy), and the rate of myocardial relaxation in diastole (lusitropy).

Sympathomimetics are substances that stimulate the sympathetic nervous system, and those found endogenously in humans are catecholamines, which act as both neurotransmitters and hormones. Other Rate commonly used substances, such as ephedrine and limiting phenylephrine, are not catecholamines but still have a step sympathomimetic effect.

Catecholamines consist of a catechol (originally distilled from the plant extract catechin), which is a benzene ring with hydroxyl groups at the 3 and 4 positions, and an intermediate ethyl chain with a terminal amine. The length and

Figure 1 composition of the side chain largely Benzene-3,4-diol determine the properties and receptor affinity of the compound. Naturally occurring endogenous catecholamines include dopamine, adrenaline (epinephrine) and noradrenaline (norepinephrine). The British Approved Name (BAN) for adrenaline and noradrenaline are in common use locally, but the International Nonproprietary Name (INN) epinephrine and norepinephrine are also used interchangeably in this chapter. Dobutamine, isoprenaline and dopexamine are examples of synthetic catecholamines in clinical use. Endogenous catecholamines are synthesised from the amino acid tyrosine (some of which is derived from phenylalanine), to form L-Dihydroxyphenylalanine (L-

Figure 2 Biosynthetic pathway of endogenous catecholamines. Inotropes Dr F Schneider DOPA), in a rate-limiting step. L-DOPA is then converted further to dopamine, norepinephrine and epinephrine, which act at dopaminergic and adrenergic receptors respectively. Dopamine has mostly paracrine and endocrine functions, suppressing the central release of thyroid stimulating hormone (TSH) and prolactin, acting on dopamine receptors in the chemoemetic trigger zone (CETZ) as well as regulating vascular tone in renal and other specialist vascular beds. Noradrenaline is the neurotransmitter involved in signalling at almost all sympathetic nerve terminal Figure 2 Synthesis of epinephrine (adrenaline) synapses. The long postganglionic sympathetic neurons have varicosities along the terminal branches, filled with synaptic vesicles that synthesise and release noradrenaline. When an action potential reaches the terminal synapse, voltage-gated calcium channels are opened, rapidly increasing local intracellular calcium concentrations, which leads to fusion of the vesicle with the cell wall and exocytosis of noradrenaline in to the synaptic cleft. Noradrenaline release also creates an autoinhibitory feedback mechanism via pre- synaptic 2 receptors (fig. 3). Adrenaline is predominantly synthesised and stored in the chromaffin cells of the adrenal medulla, and it functions as a hormone acting on distal targets following activation of the sympathetic nervous system. It is the main regulator of the “flight or fight” response. Figure 3 - Noradrenaline (NA) release and feedback control via inhibitory presynaptic 2 receptors. Rang & Dale's Pharmacology Receptors 8Ed, Elsevier 2016

Catecholamines act via cell membrane G protein-coupled receptors in various tissues, of which there are three -adrenoceptor subtypes (1, 2, 3) and two main -adrenoceptor subtypes (1, 2), which are further differentiated in to three subclasses (1A, 1B, 1D and 2A, 2B, 2C). There are at least five subtypes of dopamine receptors, but these are more easily considered as D1-like or D2-like. When a catecholamine binds to the peptide chain of the receptor, a conformational change in the G protein initiates the production of a second messenger: inositol triphosphate (IP3) in 1, and cyclic adenosine monophosphate (cAMP) in  receptors. This ultimately leads to an increase in intracellular calcium and subsequent effect determined by the cell type. The exception is the inhibitory 2 G protein, where stimulation causes a drop in cAMP and intracellular calcium levels.

1 receptors are found in high concentration in vascular smooth muscle and activation in arterioles causes an increase in peripheral vascular resistance, whereas in the venous system, activation decreases venous capacitance, and increases venous return and cardiac preload. They also mediate direct vasoconstriction of pulmonary arteries and are found in low density in cardiac ventricular muscle, where they have some inotropic effect.

06 - 2 Inotropes Dr F Schneider

2 receptors form a complex arrangement of mostly “negative feedback” mechanisms, which attenuate the sympathetic response and generally cause a lowering of blood pressure.

1 receptors are concentrated in atrial and ventricular cardiac muscle, where stimulation results in positive inotropy, chronotropy, and lusitropy. Although this increases cardiac performance and output, it comes at the cost of increased myocardial work and oxygen demand.

2 receptors in the heart are found mostly in the atria, where stimulation predominantly causes an increased chronotropic effect, with a lesser inotropic effect due to the decreased receptor density on the ventricles. Receptors in skeletal muscle arteriolar beds cause vasodilatation and improved muscular blood flow upon stimulation, with an accompanying drop in peripheral vascular resistance. In non-cardiovascular clinical application, they are targeted for the treatment of bronchospasm (bronchial smooth muscle relaxation) and premature labour (uterine muscle).

3 receptors enhance lipolysis and thermogenesis when stimulated and are involved in negative feedback mechanisms that are less well understood. Stimulation may oppose 1 effects, with a decrease in inotropy.

D1 receptors in the periphery are found in the renal vascular bed and regulate vasodilation. Centrally they are involved in extrapyramidal activity. D2 receptors inhibit further noradrenaline release peripherally, and reduce pituitary hormone output centrally.

Receptor Location Action when stimulated Mechanism Subtype

 1 Vascular smooth muscle Vasoconstriction Gq-coupled phospholipase C activated  IP3 Ca2+

2 Throughout nervous Sedation, analgesia, attenuation Gi-coupled adenylate cyclase system of sympathetic response inhibited  cAMP

 1 Heart + inotropy/chronotropy Gs-coupled adenylate cyclase activated  cAMP Platelets Platelet aggregation

2 Vascular smooth muscle, Smooth muscle relaxation Gs-coupled adenylate cyclase bronchi, uterus activated  cAMP

Heart + chronotropy

3 Adipose tissue lipolysis Gs-coupled adenylate cyclase activated  cAMP

D 1 Peripherally Vasodilatation of renal and Gs-coupled adenylate cyclase mesenteric activated  cAMP CNS Extrapyramidal activity

2 Peripherally Inhibit NA release Gi-coupled adenylate cyclase CNS pituitary hormone output inhibited  cAMP

Table 1 Actions and mechanisms of adrenoceptors. IP3 = Inositol triphosphate, cAMP = cyclic adenosine monophosphate, NA = noradrenaline, CNS = central nervous system.

06 - 3 Inotropes Dr F Schneider Naturally Occurring Inotropes

Dopamine acts both directly and indirectly. The absence of functional groups on the ethylamine sidechain allow it to enter sympathetic nerve terminals and displace noradrenaline from storage vesicles, causing an adrenergic effect, as long as noradrenaline stores have not been depleted. Figure 4 Dopamine Direct function (at doses around 5 g/kg/min) is via binding to dopamine receptors. Dopamine’s structure does not give it great affinity for  and  receptors, but at doses up to 10-20 g/kg/min, 1 receptors may be stimulated, causing increased heart rate, contractility and cardiac output. At even higher doses (>20 g/kg/min),  effects predominate, with peripheral vasoconstriction and increased systemic vascular resistance and venous return. Dopamine has therefore been described as a general inotrope-vasopressor, but its wide and unpredictable dosage range, as well as reliance on indirect mechanism of action, usually make it a suboptimal choice of inotrope. In addition, it is a potent emetogenic, supresses prolactin release (impairing immunity) and TSH release. The “renoprotective” benefit of dopamine has long since been convincingly disproven, despite its continued use in certain centres. Urine output in these patients had likely increased due to the diuretic effect of dopamine (inhibiting renal tubular reabsorption of sodium), rather than improved renal perfusion. If anything, dopamine causes maldistribution of blood flow from the renal medulla to the cortex, and may worsen renal outcomes.

Noradrenaline differs from dopamine by the addition of a single hydroxyl group on the ethylamine sidechain, making it a direct-acting drug with a high affinity for  receptors and moderate affinity for 1 receptors, without much 2 effect. This makes it a potent vasoconstrictor via 1 agonism (and lack of 2 vasodilatation) as well Figure 5 Noradrenaline as a mild inotrope via a moderate 1 effect. It is arguably the agent of choice in states of distributive shock, such as the systemic inflammatory response syndrome (SIRS) or sepsis. It is available in South Africa, but can be complicated to obtain for routine clinical use.

Adrenaline is formed from noradrenaline, with the addition of a methyl group on the terminal amine, greatly increasing affinity for both 1 and 2 receptors. At lower doses it acts predominantly as a  agonist and inotrope, with some vasopressor action. At higher doses (around 1g/kg/min) the 1 vasopressor activity dominates, but is not as potent as noradrenaline, due to the offset vasodilation via 2 Figure 6 Adrenaline activity. Adrenaline is readily available and in common use globally. Its positive chronotropic and inotropic action causes increased cardiac workload, and together with additional arrhythmogenicity, it may put patients with ischaemic heart disease at risk. Plasma glucose is raised by stimulating glycogenolysis, lipolysis and gluconeogenesis, and may also be affected by changes in insulin secretion (increased by 2, but overridden by  effects). Although it is a significant vasopressor, lactate rise is usually due to increased glycolytic flux rather than vasoconstriction and anaerobic metabolism.

06 - 4 Inotropes Dr F Schneider Adrenaline is recommended at a dose of 1mg every 2-4 minutes, as part of the resuscitation guidelines in cardiac arrest, where it is hoped to function as a pure vasopressor and intended to direct blood supply to vital organs.

Pharmacokinetics, metabolism and administration. Endogenous catecholamines have short half-lives of around a minute, due to diffusion away from their sites of action, and efficient metabolism by one of two enzymatic pathways. Monoamine Oxidase (MAO) is present in high concentrations in nerve terminals, whereas Catechol-O-Methyl-Transferase (COMT) degradation occurs in the liver and kidneys. Both transformations usually occur, producing vanillylmandelic acid (VMA) from adrenaline and noradrenaline, and homovanillic acid from dopamine. Due to the short half-life and efficient metabolism, adrenaline and noradrenaline are normally given by continuous infusion at a dose range of 0.01 – 0.5 g/kg/min, and dopamine started around 1 – 5 g/kg/min. Titration of doses should occur according to clinical effect, aiming to achieve a pre-determined target, for example, a mean arterial pressure (MAP) of around 60mmHg. Extravasation can cause tissue necrosis, so infusions are given via central venous catheters in all but emergency situations. Adrenaline doses above 1 g/kg/min are unlikely to produce additional benefit, as all receptors are maximally occupied. Adequacy of circulating cortisol levels, desensitisation and downregulation of receptors may be more important factors in these poor responders.

Synthetic Inotropes Of the synthetically produced agents, only isoprenaline, dobutamine and dopexamine are classified as catecholamines.

Isoprenaline is now rarely found to be in clinical use, due to manufacturing issues. It is a pure  agonist and was favoured for its chronotropy (useful in chemical pacing of bradycardias and denervated hearts) and inotrope-vasodilator action (useful postoperatively in paediatric cardiac patients unable to tolerate Figure 7 Isoprenaline increased afterload).

Dobutamine resembles dopamine but has a large hydrocarbon tail which ensure it is direct-acting and increases  receptor selectivity. It was designed to be a pure  agonist and has been termed an “inodilator” due to the inotropic effect at 1 receptors, combined with Figure 8 Dobutamine the afterload-reducing vasodilatory effect of 2 receptor stimulation in the skeletal muscle vascular beds. It also increases atrioventricular conduction and may precipitate arrhythmias, or increase the ventricular response rate in patients with atrial fibrillation or flutter. It is used in the treatment of low cardiac output states in heart failure and cardiac surgery, at a dose range of 1 – 20 g/kg/min. It can also be used for cardiac stress testing as an alternative to exercise.

06 - 5 Inotropes Dr F Schneider

Dopexamine is structurally similar to dopamine and dobutamine, with potent 2 agonism and minimal 1 effects, as well as potent D1 agonism with minimal D2 and no 1 action. It causes positive inotropic effects due to cardiac 2 stimulation, which together with reduced regional vascular resistance, increases splanchnic blood flow. It is now seldom used clinically.

Phenylephrine is not a catecholamine, due to the loss of a hydroxyl group from the benzene ring, but otherwise looks identical to adrenaline. This relatively minor structural change prevents it binding at  receptors, and it is a pure  agonist, causing an increase in systemic vascular resistance and blood Figure 9 Phenylephrine pressure. It is far less potent than adrenaline, and must be given in 10-fold higher doses (50 – 100g boluses intravenously). Degradation by COMT is also less effective, meaning the duration of action is longer. It should be used with caution, or not at all, in the setting of relative bradycardia or decreased inotropic states, where a  agonist should be considered in order to avoid precipitating acute cardiac failure.

Ephedrine is a naturally occurring stimulant in Ephedra plants, but is manufactured synthetically for clinical use. The absence of hydroxyl groups means that it is lipid soluble enough to enter neurons and act indirectly by releasing noradrenaline, its major mechanism of action. It is far less potent as a direct agonist and 1000-fold doses are required, also leading to rapid depletion of stored noradrenaline. It is not degraded by MAO or COMT and therefore has a longer duration of action. Ephedrine causes a mild increase in inotropy and vasoconstriction when given in intravenous boluses of 5 – 10mg. It may become ineffective after repeated doses or in patients in whom noradrenaline stores are depleted.

Amphetamines also have a benzene ring with no hydroxyl group, are highly lipid soluble and penetrate the blood-brain-barrier with ease. Although they have no direct adrenoreceptor effect, they displace catecholamines from neuronal storage vesicles and can cause central release of large amounts of catecholamines. Originally developed as medication for appetite suppression and mood disorder, they have subsequently mostly become drugs of abuse.

Phosphodiesterase (PDE) inhibitors are positive inotropes that are not dependant on adrenoceptor activation, as they increase the intracellular action of cAMP and cyclic guanosine monophosphate (cGMP) by preventing their degradation. This may be particular useful in cardiac failure when downregulation of  receptors has occurred. The selective PDE III inhibitor milrinone allows accumulation of cAMP in the cardiac myocyte, increasing cardiac contractility, enhancing left ventricular relaxation and improving early ventricular filling. Conversely, in smooth muscle, cAMP prevents calcium release and promotes smooth muscle relaxation and reduced peripheral and pulmonary vascular resistance.

Digoxin causes a modest increase in contractility by reversibly binding to Na+-K+-ATPase in the cardiac myocyte, which leads to increased availability of intracellular calcium and increased contractility.

Levosimendan is a myocardial calcium sensitiser and inodilator, which improves contractility without increasing intracellular calcium or cAMP, and thereby doesn’t increase myocardial oxygen demand. 06 - 6 Inotropes Dr F Schneider

2 Table

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ClassificationComparative and Pharmacology of Sympathomimetics.

From

Anesthetic in Pharmacology Physiology Stoelting's and Wolters Ed, 5 Kluwer Practice, 2015

06 - 7 Inotropes Dr F Schneider Notes

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