Parasympathetic Nervous System

The parasympathetic nervous system (PNS) is made up of pre- and post-ganglionic fibres. The pre-ganglionic fibres arise from two locations (see Figure 13.1):

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  Cranial nerves (III, VII, IX, X) – which supply the eye, salivary glands, heart, bronchi, upper gastrointestinal (GI) tract (to the splenic flexure) and ureters

  
  
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  Sacral fibres (S2, 3, 4) – which supply distal bowel, bladder and genitals.

All these fibres synapse within ganglia that are close to, or within, the effector organ. The post-ganglionic neurone releases acetylcholine (ACh), which acts via nicotinic receptors.

Figure 13.1 Simplified diagram of the autonomic nervous system (ANS).

The PNS may be modulated by anticholinergics (see Chapter 19) and anticholinesterases (see Chapter 12).

Sympathetic Nervous System

The sympathetic nervous system (SNS) is also made up of pre- and post-ganglionic fibres. The pre-ganglionic fibres arise within the lateral horns of the spinal cord at the thoracic and upper lumbar levels (T1–L2) and pass into the anterior primary rami, and via the white rami communicans into the sympathetic chain or ganglia where they may either synapse at that or an adjacent level, or pass anteriorly through a splanchnic nerve to synapse in a prevertebral ganglion (see Figure 13.2). The unmyelinated post-ganglionic fibres then pass into the adjacent spinal nerve via the grey rami communicans. They release noradrenaline, which acts via adrenoceptors.

Figure 13.2 Various connections of the sympathetic nervous system (SNS). DRG, dorsal root ganglion; APR, anterior primary rami; WRC, white rami communicans; GRC, grey rami communicans; PVG, prevertebral ganglion; SC, sympathetic chain.

The adrenal medulla receives presynaptic fibres that synapse directly with its chromaffin cells using ACh as the transmitter. It releases adrenaline into the circulation, which, therefore, acts as a hormone, not a transmitter.

Post-ganglionic sympathetic fibres release ACh to innervate sweat glands.

All pre-ganglionic ANS fibres are myelinated and release ACh, which acts via nicotinic receptors (see Table 13.1).

Presentation and Uses

Adrenaline is presented as a clear solution containing 0.1–1 mg.ml⁻¹ for administration as a bolus in asystole or anaphylaxis or by infusion (dose range 0.01–0.5 µg.kg⁻¹.min⁻¹) in the critically ill with circulatory failure. It may also be nebulised into the upper airway where its vasoconstrictor properties will temporarily reduce the swelling associated with acute upper airway obstruction. A 1% ophthalmic solution is used in open-angle glaucoma, and a metered dose inhaler delivering 280 µg for treatment of anaphylaxis associated with insect stings or drugs. In addition, it is presented in combination with local anaesthetic solutions at a strength of 1 in 80,000–200,000.

Mechanism of Action

Adrenaline exerts its effects via α- and β-adrenoceptors. α₁-Adrenoceptor activation stimulates phospholipase C (via G_q), which hydrolyses phosphatidylinositol bisphosphate (PIP₂). Inositol triphosphate (IP₃) is released, which leads to increased Ca²⁺ availability within the cell. α₂-Adrenoceptor activation is coupled to G_i-proteins that inhibit adenylate cyclase and reduce cAMP concentration. β-Adrenoceptors are coupled to G_s-proteins that activate adenylate cyclase, leading to an increase in cAMP and specific phosphorylation depending on the site of the adrenoceptor.

Effects

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  Cardiovascular – the effects of adrenaline vary according to dose. When administered as a low-dose infusion, β effects predominate. This produces an increase in cardiac output, myocardial oxygen consumption, coronary artery dilatation and reduces the threshold for arrhythmias. Peripheral β effects may result in a fall in diastolic blood pressure and peripheral vascular resistance. At high doses by infusion or when given as a 1 mg bolus during cardiac arrest, α₁ effects predominate causing a rise in systemic vascular resistance. It is often used in combination with local anaesthetics to produce vasoconstriction before dissection during surgery. When used with halothane, the dose should be restricted to 100 µg per 10 minutes to avoid arrhythmias. It should not be infiltrated into areas supplied by end arteries lest their vascular supply become compromised. Extravasation can cause tissue necrosis.

  
  
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  Respiratory – adrenaline produces a small increase in minute volume. It has potent bronchodilator effects although secretions may become more tenacious. Pulmonary vascular resistance is increased.

  
  
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  Metabolic – adrenaline increases the basal metabolic rate. It raises plasma glucose by stimulating glycogenolysis (in liver and skeletal muscle), lipolysis and gluconeogenesis. Initially insulin secretion is increased (a β₂ effect) but is often overridden by an α effect, which inhibits its release and compounds the increased glucose production. Glucagon secretion and plasma lactate are also raised. Lipase activity is augmented resulting in increased free fatty acids, which leads to increased fatty acid oxidation in the liver and ketogenesis. These metabolic effects limit its use, especially in those with diabetes. Na⁺ reabsorption is increased by direct stimulation of tubular Na⁺ transport and by stimulating renin and, therefore, aldosterone production. β₂-Receptors are responsible for the increased transport of K⁺ into cells, which follows an initial temporary rise as K⁺ is released from the liver.

  
  
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  Central nervous system – it increases MAC and increases the peripheral pain threshold.

  
  
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  Renal – renal blood flow is moderately decreased and the increase in bladder sphincter tone may result in difficulty in micturition.

Kinetics

Adrenaline is not given orally due to inactivation. Subcutaneous absorption is less rapid than intramuscular. Tracheal absorption is erratic but may be used in emergencies where intravenous access is not available.

Adrenaline is metabolised by mitochondrial MAO and catechol O-methyl transferase (COMT) within the liver, kidney and blood to the inactive 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid or VMA) and metadrenaline, which is conjugated with glucuronic acid or sulfates, both of which are excreted in the urine. It has a short half-life (about 2 minutes) due to rapid metabolism.

Presentation and Uses

Noradrenaline is presented as a clear solution containing 0.2–2 mg.ml⁻¹ noradrenaline acid tartrate, which is equivalent to 0.1–1 mg.ml⁻¹ of noradrenaline base, and contains the preservative sodium metabisulfite. It is used as an intravenous infusion (dose range 0.05–0.5 µg.kg⁻¹.min⁻¹) to increase the systemic vascular resistance.

Mechanism of Action

Its actions are mediated mainly via stimulation of α₁-adrenoceptors but also β-adrenoceptors.

Effects

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  Cardiovascular – the effects of systemically infused noradrenaline are slightly different from those of endogenous noradrenaline. Systemically infused noradrenaline causes peripheral vasoconstriction, increases systolic and diastolic blood pressure and may cause a reflex bradycardia. Cardiac output may fall and myocardial oxygen consumption is increased. A vasodilated coronary circulation carries an increased coronary blood flow. Pulmonary vascular resistance may be increased and venous return is increased by venoconstriction. In excess it produces hypertension, bradycardia, headache and excessive peripheral vasoconstriction, occasionally leading to ischaemia and gangrene of extremities. Extravasation can cause tissue necrosis. Endogenously released noradrenaline causes tachycardia and a rise in cardiac output.

  
  
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  Splanchnic – renal and hepatic blood flow falls due to vasoconstriction.

  
  
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  Uterus – blood flow to the pregnant uterus is reduced and may result in fetal bradycardia. It may also exert a contractile effect and cause fetal asphyxia.

  
  
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  Interactions – despite being a direct-acting sympathomimetic amine, noradrenaline should be used with caution in patients taking monoamine oxidase inhibitors (MAOIs) as its effects may be exaggerated and prolonged.