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Author: Zachary R. Noel, PharmD, BCPS

What do the following have in common: hurricanes and FDA regulations, poor manufacturing practices and low-margin generic products. Each has played a role in the evolving and ongoing drug shortage crisis that has been a thorn in the side of hospital administrators, a thief of health-systems budgets, and a threat to the care of patients.1 Since 2010, the revolving door of unavailable drugs has forced healthcare workers to do (and spend) more with less. As such, pharmacists are being called upon to come up with creative and savvy solutions to combat the drug shortage crisis, all while ensuring patient care is not compromised. Few areas of acute care practice remain unaffected, including the cardiac care unit (CCU).  Fluids, vasopressors, inotropes, amiodarone, electrolytes, and cardiovascular imaging and procedural medications are just a few of the practice-altering shortages our healthcare system has been faced with.2 The intent of this blog is to highlight recent, current, or probable drug shortages that have direct impact on cardiovascular care, as well as to provide alternative medication options and clinical caveats for consideration. This blog will not detail all cardiovascular medication shortages, but will seek to address those most pertinent to current practice.


Cardiovascular Imaging and/or Procedural Medications
Abciximab is used almost exclusively in the cardiac cath lab in the setting of patients presenting with acute coronary syndrome and high thrombus burden. Alternative glycoprotein IIb/IIIa inhibitors include eptifibatide and tirofiban; however, there are important pharmacokinetic and pharmacodynamic differences between these medications that must be taken into consideration.3  Abciximab irreversibly binds GP IIb/IIIa. Platelet function is restored within 24-48 hours of discontinuing abciximab.  On the contrary, eptifibatide and tirofiban reversibly bind GP IIb/IIIa, thus platelet function is restored within 4-8 hours of discontinuation.4 Abciximab does not require dose adjustment for renal dysfunction, whereas eptifibatide and tirofiban must be dose adjusted for creatinine clearance less than 50 and 60 ml/min, respectively, and dosing in end stage renal disease (ESRD) is not well established.5-

Aminophylline is a xanthine derivative and used as a reversal agent for patients receiving regadenoson for nuclear imaging studies (e.g., nuclear stress test). The need to reverse the effects of regadenoson is infrequent but occasionally warranted in patients with a history of lung disease (e.g., asthma or chronic obstructive pulmonary disease).7 Intravenous caffeine, which is also a xanthine derivative, at a dose of 60 mg is approximately equivalent to IV aminophylline 100 mg.7-8 Unfortunately, IV caffeine has also been on shortage. Fortunately, oral caffeine (e.g., caffeine supplements or soda) is also an effective substitute and can be used for patients experiencing mild-moderate symptoms.7-8

Isoproterenol is a non-selective beta-agonist that produces positive inoptropic and chronotropic effects, as well as vasodilation. It has a short half-life (~2.5 – 5 minutes) and exhibits potent effects on AV nodal conduction. It is predominately used for electrophysiology procedures, including catheter ablations and provocation testing. Less commonly, it is used for symptomatic bradycardia or bradyarrhythmias following heart transplantation.9-10 Isoproterenol has been used since the 1940’s, but in recent years the cost has increased over 500%.11 Alternative medications to consider include epinephrine, dopamine, and dobutamine. Unfortunately, each of these have distinct limitations that must be taken into consideration. Epinephrine, unlike isoproterenol, is a potent alpha-receptor agonist and has little direct effect on the AV node. This makes it less useful for electrophysiology procedures where patients generally do not need hemodynamic support. Similar effects are noted with dopamine. Dobutamine, which was originally developed in pursuit of a positive inotrope with less impact on heart rate and blood pressure, is a potential option but not without limitation.12 At equipotent inotropic doses, dobutamine only produces 25% the chronotropic effects of isoproterenol.12 This has made identifying an alternative medication for use in the electrophysiology lab difficult; however, several institutions have implemented cost-avoidance initiatives, such as making more dilute IV preparations and extending the expiration dating.13-14
For symptomatic bradyarrhythmias, it is generally feasible to use alternative pharmacologic and nonpharmacologic interventions to increase heart rate.9 Temporary pacing wires can effectively restore heart rate until a longer-term solution is available, although the cost-effectiveness of this strategy has not been explored. Additionally, in patients who are hypotensive, dopamine or epinephrine are more appropriate and cost-effective therapies.


Electrolytes
Electrolyte shortages are among the most challenging and worrisome for healthcare professionals. Calcium, magnesium, and potassium shortages are an ever-present reality, and hospitals have been forced to curb their use in order to reserve supply for the most critical situations (e.g., life threatening arrhythmias). As such, aggressive oral electrolyte replacement protocols are being used whenever possible. When repleting electrolytes orally, it is important to take into consideration both the salt formulation as well as bioavailability. Calcium, for example, can be replaced orally using products such as calcium carbonate or calcium citrate, but each of these salt forms has a varying amount of elemental calcium (Table 1). In addition, the bioavailability is only ~25%, although this is highly variable depending on vitamin D levels, age, and salt formulation, among other factors.15 All-in-all, ~2-4 gm/d of calcium carbonate or citrate is commonly used for repletion. For magnesium, our institution proactively orders oral magnesium oxide 400-800 mg BID-TID in patients receiving IV diuresis. When repleting potassium orally, it’s important to split up doses > 40 mEq into divided doses every 2-4 hours to minimize gastrointestinal intolerance. In addition, repleting magnesium prior to giving potassium helps reduce the amount that is wasted.16

Table 1: Elemental Calcium in Calcium Products
Calcium Salt Percent Calcium Elemental Calcium (mg/gram)
Calcium chloride 27% 272
Calcium gluconate 9% 93
Calcium carbonate 40% 400
Calcium citrate 21% 211


Inotropes
Dobutamine shortages have posed challenges in the management of both cardiogenic shock and acute decompensated heart failure. Dobutamine has a short half-life (~5-10) minutes and does not need to be renally dose adjusted, making it easily titratable.17 Milrinone, a phosphodiesterase type-3 inhibitor, was on shortage briefly in 2016 but has since been consistently available.2, 18 Milrinone is a logical alternative to dobutamine because it produces similar inotropic effects, although it produces more vasodilation than dobutamine.19 Milrinone has a much longer half-life (~40 minutes) and is prolonged with renal dysfunction. In patients who may not tolerate the vasodilatory effects of milrinone, epinephrine can be used as an alternative. Dopamine may also be considered, but due to disadvantages detailed elsewhere, we tend to avoid using it.


Miscellaneous
Intravenous diltiazem, which is predominately used for acute rate control in patients with supraventricular tachycardia (SVT) and normal left ventricular function, can be replaced by a number of alternative medications. Metoprolol, esmolol, and verapamil are all therapeutic alternatives to achieve rate control in SVT. Given the low cost and ease of access, IV metoprolol is commonly used.

Intravenous amiodarone is commonly used for the acute management of atrial fibrillation, ventricular tachycardia, and ventricular fibrillation. Table 2 contains a list of potential alternative therapies to consider when amiodarone is unavailable.  For more information and pearls on using amiodarone, check out our recent blog.

Table 2: Alternative Options to Amiodarone for Acute Management of Arrhythmias
Arrhythmia Alternatives to Amiodarone Important Considerations
Acute management of atrial fibrillation Cardioversion if unstable

Ibutilide 1 mg over 10 minutes

Beta-blockers, calcium channel blockers if hemodynamically stable

Digoxin

QTc prolongation; shortage of magnesium may make administering ibutilide an unsafe option
Hemodynamically stable monomorphic ventricular tachycardia Procainamide 10-17 mg/kg ideal body weight (or 1000 mg) followed by 1-4 mg/min) Max infusion rate 50 mg/min

Hypotension with bolus dose

QRS and QT prolongation

Adjust for renal dysfunction

Pulseless ventricular tachycardia/ventricular fibrillation Lidocaine 1.5 mg/kg

 

Table 3: Alternatives for Cardiovascular Medications Impacted by Drug Shortages
Implicated Intravenous Medications Alternative Drug(s)*
Abciximab Eptifibatide, tirofiban
Aminophylline Caffeine (oral or IV)
Amiodarone Acute management of ventricular arrhythmias: procainamide, lidocaine, sotalol

Acute management of atrial arrhythmias: oral amiodarone (if hemodynamically stable), ibutlilide, sotalol, beta-blockers, calcium channel blockers

Diltiazem Esmolol, metoprolol, verapamil
Dobutamine Milrinone
Isoproterenol Transvenous pacing

Dobutamine

Dopamine, epinephrine

Nitroglycerin SL nitroglycerin, nitroprusside
Nitroprusside Nitroglycerin, nicardipine or clevidipine
*drug selection is based on patient-specific factors

 

Sources for Up-To-Date Information on Drug Shortages Website
American Society of Health-Systems Pharmacy https://www.ashp.org/drug-shortages/current-shortages
Food and Drug Administration https://www.accessdata.fda.gov/scripts/drugshortages/


Have other drugs that you’d like to see highlighted on the drug shortages blog? Feel free to drop a comment in the blog and we’ll update the blog to include the information.

Zachary R. Noel, PharmD, BCPS

Dr. Noel is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in cardiology at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @ZacNoelCardsRx.

 

References:

  1. Drug shortages roundtable: Minimizing the impact on patient care. American Journal Of Health-System Pharmacy [serial online]. June 2018;75(11):816-820. Available from: CINAHL with Full Text, Ipswich, MA. Accessed June 19, 2018.
  2. Current Drug Shortages. ASHP. Accessed June 19, 2018 https://www.ashp.org/drug-shortages/current-shortages.
  3. Kleiman N. Pharmacokinetics and pharmacodynamics of glycoprotein IIb-IIIa inhibitors. American Heart Journal [serial online]. October 1999;138(4 Pt 2):263-275. Available from: MEDLINE, Ipswich, MA. Accessed June 19, 2018.
  4. Tardiff B, Jennings L, Kleiman N, et al. Pharmacodynamics and pharmacokinetics of eptifibatide in patients with acute coronary syndromes: prospective analysis from PURSUIT. Circulation [serial online]. July 24, 2001;104(4):399-405. Available from: MEDLINE, Ipswich, MA. Accessed June 19, 2018.
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  7. Doran J, Sajjad W, Schneider M, Gupta R, Mackin M, Schwartz R. Aminophylline and caffeine for reversal of adverse symptoms associated with regadenoson SPECT MPI. Journal Of Nuclear Cardiology: Official Publication Of The American Society Of Nuclear Cardiology [serial online]. June 2017;24(3):1062-1070. Available from: MEDLINE, Ipswich, MA. Accessed June 19, 2018.
  8. Jolly A, Thomas G. Intravenous caffeine: An alternative to aminophylline to reverse adverse effects during regadenoson myocardial perfusion imaging. Journal Of Nuclear Cardiology: Official Publication Of The American Society Of Nuclear Cardiology [serial online]. June 2017;24(3):1071-1074. Available from: MEDLINE, Ipswich, MA. Accessed June 19, 2018.
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  12. Tuttle RR, Mills J. Dobutamine: development of a new catecholamine to selectively increase cardiac contractility. Circ Res 1975; 36(1):185-196
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  14. Bloomstein D, Serra M, Baviskar S, Winters S. Cost Avoidance Utilizing a Batching Process for Isoproterenol. P & T: A Peer-Reviewed Journal For Formulary Management [serial online]. September 2016;41(9):560-561. Available from: MEDLINE, Ipswich, MA. Accessed June 19, 2018.
  15. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Washington (DC): National Academies Press (US); 2011.
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The Short End of the Stick: Practical Management of Cardiovascular Drug Shortages

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