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