Thursday, October 9, 2014

The Wonders and Woes of Parenteral Hydralazine

As I have developed a method to my practice (and madness) as an emergency medicine pharmacist, there are certain medications that, for me, fall under one of two categories: those that I have grown to love…and those that I have grown to not be a fan of and can generally live without, even in the absence of drug shortages.

For me, parenteral hydralazine falls under the latter category.


Why?

As many of us already know, hydralazine is a potent vasodilator that has direct actions on the vascular smooth muscle, leading to arterial vasodilation primarily. It is thought to work through inhibition of the release of calcium into smooth muscle cells within the vasculature through a number of mechanisms, which include induction of cyclic guanosine monophosphate (cGMP), generation of nitric oxide, and hyperpolarization of cell membranes.

The issues that many encounter related to the effects of hydralazine are mainly due to its pharmacokinetic properties. It has an onset of action of upwards of 20 minutes, with peak effects last for 60 minutes. However, duration of action is somewhat prolonged and unpredictable compared to other parenteral agents available for hypertensive crises; the effects of hydralazine can persist for upwards of eight hours. A review article published (ironically) in the Journal of Emergency Medicine nearly two decades ago highlights some of the factors associated with these effects (1), which includes the fact that the active metabolites of hydralazine may tend to stick around for some time. Another possible reason is that the drug may actually bind to the tissue within the arterial wall itself, which has been demonstrated in a number of animal studies. A third plausible explanation is the idea that hydralazine may have a continuous effect on endothelium-derived relaxing factor, which is a molecule that signals the cells within the smooth muscle to dilate.

In addition, the adverse effects of hydralazine are not benign either. Hydralazine is generally not recommended in patients with cardiovascular comorbidities such coronary artery disease, aortic dissection, and valvular dysfunction, as it can cause stimulation of the sympathetic nervous system, leading to exacerbation of oxygen consumption in a myocardium (which may be already compromised to begin with) as well as an increase in heart rate. In addition, in patients with disrupted cerebral autoregulation, hydralazine has been demonstrated to be associated with increasing intracranial pressure (2-4).

Some may argue that hydralazine does have a specific role within the emergency department, especially when it comes to managing patients who may present with pregnancy-associated hypertension. However, hydralazine is not gentle in its adverse effect profile, as patients may experience severe hypotension and complications associated with birth. If labetalol fails or is not an option, reasonable alternative agents that may be used in this setting include nicardipine and sodium nitroprusside (5-8).

And for those who still wish to use parenteral hydralazine for admitted patients, great vigilance should be taken to ensure that the use of this agent is appropriate. One retrospective study analyzed prescribed orders of parenteral hydralazine in 94 patients over a six-month period to evaluate clinical parameters prior to and following administration of hydralazine, including evidence of target-organ damage and/or symptoms associated with severe hypertension, change in blood pressure and heart rate, and the incidence of adverse effects (9). The investigators found that only 2% of all patients who were prescribed hydralazine had documented evidence of hypertensive crisis. Over 80% of all doses of hydralazine that were administered within this time frame were associated with a reduction in systolic blood pressure of less than 25%. Of the 16 patients who experienced an adverse effect, most were related to hypotension, with six of those patients experiencing a decrease in systolic blood pressure by at least 65 mmHg. In addition, investigators of a recently published multicenter study found that hydralazine was commonly implicated with profound hypotension in the critical care setting (10).

As with anything, increasing provider awareness and education is essential, and verifying that the right circumstances are in place with thorough patient evaluation prior to administration of parenteral hydralazine, including confirmation of the fact that all possible alternatives for managing blood pressure have been optimized prior to initiation of this agent, is critical.

For now, parenteral hydralazine is in fact on a nationwide shortage and the resupply date through various manufacturers is still unknown (11). However, I am certainly not missing it in my practice in the emergency department anyway. 

References:

  1. Powers DR, Papadakos PJ, Wallin JD. Parenteral hydralazine revisited. J Emerg Med 1998; 16:191-196.
  2. Ludden TM, Shepherd AM, McNay JL, et al. Hydralazine kinetics in hypertensive patients after intravenous administration. Clin Pharmacol Ther 1980, 28:736-742.
  3. Rhoney DH, Liu-DeRyke X. Effect of vasoactive therapy on cerebral circulation. Crit Care Clin 2006; 22:221-243.
  4. Skinhoj E, Overgaard J. Effect of dihydralazine on intracranial pressure in patients with severe brain damage. Acta Med Scand Suppl 1983; 678:83-87.
  5. Emergent therapy for acute-onset, severe hypertension with preeclampsia or eclampsia. Committee Opinion No. 514. American College of Obstetricians and Gynecologists. Obstet Gynecol 2011; 118:1465-1468.
  6. Arulkumaran N, Lightstone L. Severe pre-eclampsia and hypertensive crises. Best Pract Res Clin Obstet Gynaecol 2013; 27:877-884.
  7. Magee LA, Cham C, Waterman EJ, et al. Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis. BMJ 2003; 327:955-960.
  8. Alexander JM, Wilson KL. Hypertensive emergencies of pregnancy. Obstet Gynecol Clin North Am 2013; 40:89-101.
  9. Campbell P, Baker WL, Bendel SD, et al. Intravenous hydralazine for blood pressure management in the hospitalized patient: its use is often unjustified. J Am Soc Hypertens 2011; 5:473-477.
  10. Kane-Gill SL, Leblanc JM, Dasta JF, et al. A multicenter study of the point prevalence of drug-induced hypotension in the ICU. Crit Care Med 2014; 42:2197-2203.
  11. Drug Shortages: Hydralazine Injection. American Society of Health-System Pharmacists. Available at: http://bit.ly/1oTPepf [Accessed 8 October 2014]