Sympathomimetic amines.
The sympathomimetic amines are traditionally classified according to their activity at alpha, beta ² and, more recently, dopaminergic receptors. The subclassification and effects of stimulation at these sites are outlined in Table 1 . The drugs can be usefully visualised on a spectrum of activity according to the magnitude of their alpha 1 and beta 2 effects (Figure 1). Some of the drugs act 'indirectly' as sympathomimetic agents by stimulating the presynaptic release of noradrenaline, but most act directly at the post-synaptic receptor site.

The sympathomimetics act by stimulating the synthesis of the 'second messenger' cyclic AMP (cAMP). The intracellular concentration of cAMP determines the contractile state of the myocardium by activating protein kinase 'A' which, in turn, elevates intracellular Ca++ levels and facilitates both contraction and relaxation.

All of the sympathomimetic drugs noted here have very short half lives and must therefore be given by constant infusion. Typical dose ranges for adults are quoted, but these may need to be exceeded if either 'down-regulation' of adrenoreceptors has occurred, or the patient has had prior exposure to an alpha or beta blocking drug.

The infusion rate calculator supplied with this book can be used to calculate the infusion rates of various inotropic, vasoactive and anti-dysrhythmic drugs. The calculator can be activated by clicking on the 'Infusion' button at the left.

Dopamine.
Dopamine was introduced in the early 1970s ³ and remains one of the most important drugs available for the treatment of circulatory failure. The drug exerts its principal effects at dopaminergic, alpha 1 and beta 1 receptors. In low doses (0.5 - 2.0 mcg/kg/min), predominantly dopaminergic effects (increased renal blood flow, diuresis, natriuresis) are seen, but as the infusion rate is increased, alpha 1 (systemic vasoconstriction) and beta 1 effects become more apparent and contractility, afterload and systemic blood pressure all increase. The infusion rate can be increased to about 20 mcg/kg/min if clinically indicated.

Dobutamine.
Dobutamine ⁴ appeared in 1975. It is a drug much favoured by intensivists and cardiologists, but less so by anaesthetists. The drug exerts its principal effects at beta 1 and beta 2 receptors. Hence, in comparison to dopamine, it has no renal (dopaminergic) effects and does not cause vasoconstriction. Afterload and systemic blood pressure tend to fall when the drug is administered. The infusion rate can be increased to about 20 mcg/kg/min if clinically indicated.

Isoprenaline.
Isoprenaline was the first 'pure' beta receptor agonist to be discovered. It has pronounced beta 1 and beta 2 effects, causing a marked increase in contractility and pulse rate. It also has powerful vasodilator effects and tends to produce an undesirable fall in mean arterial pressure in many clinical situations. Other important side-effects of the drug include a tendency to cause tachyarrhythmias and the inappropriate release of hypoxic pulmonary vasoconstriction (HPV) - which may cause hypoxia unless supplementary oxygen is given. The activity profile of the drug has led to it being rarely used in the management of acute circulatory failure. It is, however, still used in the treatment of bradyarrhythmias. As part of the emergency management of complete heart block (Figure 2) an adult can be given a bolus dose of 20mcg of isoprenaline which can be repeated as necessary before pacemaking is initiated. If used in this way, it is often necessary to administer a vasopressor such as metaraminol concurrently in order to maintain blood pressure.

Noradrenaline.
Noradrenaline, together with adrenaline, is a naturally occurring sympathetic neurotransmitter. When administered therapeutically, the drug exerts its principal effects at alpha1, alpha 2 and beta 1 receptors where it is both a potent inotrope and vasoconstrictor. The clinical effects of the drug are to increase contractility, blood pressure and afterload and to lower the pulse rate. The drug has enjoyed a resurgence in popularity in recent years when used in combination with a phosphodiesterase inhibitor or, in isolation, as therapy for 'Low Systemic Vascular Resistance Syndrome' following cardiopulmonary bypass. When used in the treatment of 'Low Systemic Vascular Resistance Syndrome', noradrenaline is less likely to precipitate lactic acidosis than adrenaline ⁵. The drug is given by constant infusion in the dose range 0.1 - 1 mcg/kg/min.

Adrenaline.
Adrenaline is the second of the naturally occurring sympathetic neurotransmitters. When administered therapeutically, the drug exerts its principal effects at alpha 1, alpha 2 , beta 1 and beta 2 receptors. The clinical effects of the drug are to increase contractility, blood pressure, afterload and pulse rate. The drug is given by constant infusion in the dose range 0.1 - 1 mcg/kg/min. If given by infusion at very low doses (< 0.02 mg/kg/min) the drug has predominantly beta 1 and beta 2 effects, as the infusion rate is increased, a stimulation becomes more prominent. The drug is the most useful 'general purpose' sympathomimetic amine.

Phosphodiesterase inhibitors.
The phosphodiesterase type III inhibitors (PDEIs) inhibit the hydrolysis of cAMP and thus, as inotropes, act synergistically with the sympathomimetic agents. They are also direct-acting venous and arterial vasodilators and for this reason are also classified as 'inodilators'. The vasodilatation of the PDEIs is especially marked in the pulmonary circulation and the drugs are particularly useful if reduction of PVR is required. Unlike the sympathomimetic agents, they tend not to increase myocardial VO2. The drugs may have a specific role in modifying the hypoxic pulmonary vasoconstrictive response ⁶.

Milrinone.
Milrinone ⁷ is the most potent of the currently available PDEIs. The drug is typically used by administering a loading dose of 50 mcg/kg followed by an infusion in the dose range 0.375 - 0.75 mcg/kg/min ^{8, 9}. When used in this manner, milrinone increases CI by at least 20-30% and reduces PAOP and SVR by the same proportion. The reduction in vascular resistance is often of sufficient magnitude to require the concurrent administration of noradrenaline. PDEIs are particularly indicated in the setting of right ventricular failure, or, where a synergistic effect with sympathomimetic amines is required. They have also been shown to be of particular benefit in weaning high-risk patients from cardio-pulmonary bypass (CPB) ¹⁰.

A recent report by Haraldsson et al has demonstrated that the drug can also be administered as an aerosol. When used in this way, it is apparently devoid of any effect on SVR and, furthermore, potentiates and prolongs the pulmonary selective vasodilatory effect of inhaled prostacyclin PGI2¹⁸.

Milrinone may also have a role in attenuating the systemic inflammatory response to CPB. It has been recently reported that splanchnic perfusion and gastrointestinal pH (pHI) are better maintained, and venous endotoxin and interleukin 6 levels are significantly lower, if milrinone is administered to patients undergoing routine coronary artery grafting ¹¹.

More information on Milrinone is available from www.milrinone.com.

Amrinone.
Amrinone ^{12, 13} has a virtually identical pharmacological profile to milrinone, except that it is less potent. It has been used for the treatment of acute pulmonary hypertension in the setting of paediatric cardiac surgery ¹⁴. The drug has also been suggested as an appropriate vasodilator for the treatment of pulmonary hypertension complicating the Acute Respiratory Distress Syndrome ¹⁵.

Chronotropes.
Pulse rate can be manipulated by altering the balance between the sympathetic (acceleration) and parasympathetic (deceleration) nerve supply to the heart, or, by altering the intrinsic rhythmicity of the sinu-atrial node with a drug such as adenosine.

Beta agonists (particularly beta 1 agonists) (Table 1) can be used to accelerate the heart and increase contractility whereas beta blockers such as esmolol or metoprolol can be used to decelerate the heart and reduce contractility. In practice, it is difficult to separate the negative chronotropic and inotropic effects of the beta blockers.

Vagolytic drugs such as atropine act both peripherally and centrally to block postganglionic cholinergic (muscarinic) receptors and in high doses produce cardiac acceleration with little effect on inotropy.

Anticholinesterases such as neostigmine are occasionally used to inhibit the hydrolysis of acetyl choline, raise vagal tone and so lower the pulse rate. If the patient paralysed with a non-depolarising muscle relaxant at the time of administration of neostigmine, the drug may reverse the neuromuscular blockade.

Finally, it is worth remembering that, if baroreceptor reflexes are intact, any manoeuvre that tends to raise the blood pressure will tend to increase vagal tone and lower the pulse rate and conversely, any manoeuvre that tends to lower the blood pressure will tend to decrease vagal tone and increase the pulse rate.

Therapeutic manipulation of pulse rate is important in various clinical situations. For example, tachycardia is generally undesirable in the presence of ongoing myocardial ischaemia because left ventricular perfusion occurs largely in diastole and a short diastolic interval reduces the time available for coronary perfusion (Figure 3).

Conversely, in the presence of a valvular lesion such as aortic incompetence, there is an argument for accelerating a slow pulse rate so as to shorten the period available for regurgitant flow.

Atropine.
Atropine is an anticholinergic drug which acts both centrally and peripherally to block muscarinic receptors. In low doses, (eg 2 - 5 mcg/kg) blockade of the central (CNS) receptors may produce transient vagal stimulation resulting in a paradoxical bradycardia. At higher doses (eg 10 - 15 mcg/kg), the peripheral effects of the drug overshadow the central effects and tachycardia supervenes. The drug has an annoying tendency to precipitate AV block (usually without much effect on heart rate) when given intravenously. Atropine-induced AV block may be a particular risk in patients who have undergone cardiac transplantation ¹⁶.

Glycopyrrolate.
Glycopyrrolate can be used to counteract the effects of vagotonic drugs such as fentanyl or neostigmine. The drug is unlikely to precipitate dysrhythmias, has no central effects and has little tendency to increase the heart rate.

Adenosine.
Adenosine ¹⁷ is unique among the anti-dysrhythmic drugs (Table 2) in that it is an endogenous compound, produced as a result of the metabolism of AMP. It has an extremely short half-life (< 5 seconds), is a powerful negative chronotrope and a potent vasodilator.

As a negative chronotrope, it acts to reduce the rate of phase 4 depolarisation of the myocardial action potential (Figure 4) and decreases SA, AV and ventricular rhythmicity. It can be used therapeutically in the treatment of AV nodal tachycardia, or to produce sinus arrest during cardiac or endovascular aortic surgery.

The drug can also be used diagnostically to distinguish a supraventricular tachycardia with aberrant conduction - which may terminate with adenosine, from a ventricular tachycardia - which will not.

When used as a negative chronotrope, adenosine is given by rapid intravenous injection in the dose range 100 - 200mcg / kg. The actions of the drug are potentiated by nucleoside transport blocking agents such as dipyridamole and inhibited by methylxanthine derivatives such as aminophylline. Refer to the section on vasoactive drugs for an account of the vasodilator effects of adenosine.

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Last edited on: 24/12/2001