Vasodilators.
Vasodilator drugs are now available which can specifically 'target' different sites in the circulation (Figure 1). Some drugs, such as hydralazine, exert their primary effects on the arterial capacitance vessels - reducing both afterload and blood pressure. In contrast, nitroglycerine (glyceryl trinitrate) acts predominantly as a venodilator and reduces preload while having little effect on afterload. Sodium nitroprusside is a potent, 'mixed', vasodilator which reliably reduces both afterload and preload. Drugs such as nitric oxide and adenosine, which have extremely short half-lives, can effectively be used to target the pulmonary circulation.

The normal heart is relatively insensitive to changes in afterload, but, if ventricular function is severely impaired, cardiac output may be increased greatly by 'afterload reduction' (Figure 2). Conversely, preload reduction of the 'sick heart' may not greatly reduce cardiac output - because the slope of the Frank-Starling curve is relatively flat (Figure 3). However, the reduction in preload will decrease ventricular wall tension, which leads to a beneficial reduction in myocardial oxygen utilisation (Figure 4).

All of the parenterally-administered venodilators tend to reduce pulmonary vascular resistance and as a result, may increase venous admixture (Figure 5), inappropriately release HPV and worsen hypoxia.

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.

Nitric oxide.
Nitric Oxide (NO) is unique among the vasodilators in that it is administered by inhalation at low concentration and has such an ephemeral effect that it acts only as a pulmonary vasodilator. The drug produces a marked reduction in PVR and pulmonary artery pressures, but, tends not to release HPV inappropriately because, unlike intravenously administered agents, it is only delivered to ventilated alveoli. NO is usually administered at an inspired concentration or 10-40 ppm, and at this concentration will have no significant effect on the normal pulmonary vasculature under normoxic conditions, but will reverse hypoxia-induced pulmonary hypertension ². NO has been used extensively in the treatment of ARDS and has been shown to lower pulmonary arterial pressure, reduce PVR and reduce venous admixture ³.

Nitric oxide is also believed to be the 'Endothelium Derived Relaxing Factor' ⁴ which is released by therapeutically administered sodium nitroprusside and accounts for the vasodilating effects of this and other nitrates. NO exerts its effects by activating soluble guanylyl cyclase, which leads to an increase in cyclic GMP production and subsequent vascular smooth muscle relaxation.

Adenosine.
When administered by constant infusion at a dose of up to 200 mcg/kg/min, adenosine can be used for its vasodilatory effects. Because of its short plasma half life (< 5 seconds), the drug has a particular role as a relatively specific pulmonary vasodilator. If given at low dosage (< 50 mcg/kg/min) to patients with primary pulmonary hypertension ⁵, or normal patients following cardiopulmonary bypass ⁶, the drug produces significant reductions in pulmonary vascular resistance without affecting systemic arterial pressure. At a higher dose range, more evidence of systemic vasodilatation is seen ^{7, 8}.

The nucleoside transport blocking agent dipyridamole can be used to chronically elevate plasma adenosine levels. Patients in chronic heart failure can be improved both symptomatically and by an increase in ejection fraction and maximal oxygen consumption when treated with dipyridamole ⁹.

The drug can also be used as a negative chronotrope. Refer to the section on inotropic drugs for details of its use.

Nitroglycerine.
As a vasodilator, nitroglycerine acts predominantly on the venous side of the circulation to reduce preload. The reduction in preload is accompanied by a decrease in LV wall tension with a secondary reduction in myocardial oxygen utitilisation (Figure 4). Nitroglycerine is also a specific coronary arterial vasodilator and spasmolytic. Thus it acts beneficially on both the supply and demand sides of the myocardial oxygenation equation. In addition to increasing venous capacitance, the drug reduces PVR and tends to increase venous admixture (Figure 5). At higher dosages, nitroglycerine also reduces afterload and blood pressure and, as a result, tends to cause a reflex tachycardia.

The drug has other unwanted effects apart from the potential to cause hypoxia and tachycardia. - Tolerance to the drug may develop after a relatively short period of exposure ¹⁰, it may interfere with the anticoagulant effect of heparin ¹¹ and may also depress platelet aggregation ¹².

The use of intravenous nitroglycerine was not described until 1976 ¹³ over a 100 years after the first reports of the use of the organic nitrates in the treatment of angina pectoris ^{14, 15}. The drugs are still of primary importance in the treatment of acute myocardial ischaemia. Intravenous nitroglycerine is given by constant infusion in the dose range 0.5 - 5 mcg/kg/min.

It should be noted that a considerable amount of nitroglycerine may be absorbed onto the surface of a PAC if this route is chosen for the administration of the drug ¹⁹. If the same administration channel is subsequently used for the delivery of another infusion, clinically significant amounts of nitroglycerine may be eluted into the new infusion for a period of 30-60 minutes.

Sodium Nitroprusside.
Sodium Nitroprusside (SNP) is the most potent of the 'mixed' vasodilators. The drug must be given by constant infusion. SNP reliably reduces both afterload and preload when used in the dose range 0.5 to 8 mcg/kg/min. As with other afterload reducing agents, it tends to cause a reflex tachycardia which can be counteracted by the concurrent administration of a beta blocking drug. Because of its effect of reducing PVR, it may also inappropriately release HPV and cause hypoxia. The drug should only be used in patients in whom blood pressure is being monitored directly. There is a strong correlation between age and 'sensitivity' to the drug ¹⁶.

Cyanide toxicity is a potential complication of SNP therapy ¹⁷. It has never been reported when the infusion rate is kept below 8 mcg/kg/min. If higher rates are required, the concomitant use of a beta blocking drug should be considered. If toxicity occurs, it can be treated with sodium nitrite (5 mg/kg IV). This converts haemoglobin to methaemoglobin, which then binds cyanide radicals to form cyanmethaemoglobin.

Hydralazine.
Hydralazine acts exclusively on the arterial side of the circulation to reduce afterload. Its precise mode of action is not clear, except to say it probably does not act as a receptor antagonist because it can counteract vasoconstriction produced by a wide variety of drugs including noradrenaline, prostaglandins and serotonin. It has a pronounced tendency to cause a compensatory tachycardia which tends to limit its usefulness. This reflex (?) effect can be overridden by the concurrent administration of a beta blocking drug.

Phentolamine.
Phentolamine is a short-acting, non-selective alpha 1 and alpha 2 blocking agent. The drug is a 'mixed' vasodilator, acting on both the arterial and venous sides of the circulation, but causes a marked reflex tachycardia which limits its usefulness. The drug can be given by constant infusion in the dose range 0.5 - 5 mcg/kg/min.

Vasoconstrictors.
The commonly used vasoconstrictor drugs all have alpha 1 agonist activity, but vary in the amount of beta activity that they possess (Figure 6). As a result, all increase SVR (afterload) and blood pressure, but vary in their effect on cardiac output. The pure a agonists leave the output of the normal heart unchanged, but may significantly reduce it in the failing heart (Figure 7). As the beta activity of the vasoconstrictor is increased, so cardiac output also tends to increase.

Methoxamine.
Methoxamine is a pure alpha 1 agonist. When given as a bolus dose of 0.25 - 2mg, it has the clinical effects of increasing blood pressure and reducing the pulse rate for about 10 minutes. The drug should be used with extreme caution in patients with heart disease. - Methoxamine is a potent coronary vasoconstrictor and increases afterload without any compensatory inotropic effect. Thus, if ventricular function is impaired, or the patient has a condition such as aortic incompetence, a marked reduction in cardiac output can be precipitated (Figure 7). Unlike most of the other vasoactive drugs, it has a relatively long half life and is not suitable for use by infusion.

Metaraminol.
Metaraminol is an indirect-acting alpha 1 agonist with a minor amount of beta 1 activity. When given as a bolus dose of 0.5 - 1mgs, it has the clinical effects of increasing blood pressure and reducing the pulse rate for about 5 minutes.

Ephedrine.
Ephedrine is an indirect-acting alpha 1 and beta 1 agonist. When given as a bolus dose of 2.5 - 5mgs, it has the clinical effects of increasing blood pressure and pulse rate for 5-10 minutes.

If a sustained vasoconstrictive effect is required, noradrenaline, which has a shorter half-life than the three agents listed above, is an easier drug to administer by constant infusion.

Vasopressin.
The use of vasopressin as an alternative to noradrenaline in the treatment of phosphodiesterase inhibitor-induced hypotension has recently been described by Gold et al ¹⁸. When given by constant infusion at very low doses (0.03-0.07 units/min), these authors found the drug to be particularly effective in combating milrinone-induced hypotension.

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18. Gold JA, Cullinane S, Chen J, Oz MC, Oliver JA, Landry DW. Vasopressin as an alternative to norepinephrine in the treatment of milrinone-induced hypotension. Crit Care Med 2000 Jan;28(1):249-52

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Last edited on: 24/12/2000