Pharmacology 101: Into the Uncharted Waters of COVID-19

Pharmacology 101 is an online column designed to keep EMS providers informed on formularies, dosages, effects, applications, and current research related to medications administered in the prehospital setting. If you have a medication-related question you’d like the author to address, contact editor@emsworld.com.

Author’s note: as our knowledge of COVID-19 continues to grow and evolve, new information is always being added. Every effort has been made to present information that is up to date as of the time of writing; however, readers should always keep abreast of new information that comes to light.

At the time of this publication, there have been more than 1.2 million reported cases of COVID-19 in the United States, with more than 73,000 deaths.¹ I’d like to use the Pharmacology 101 platform to provide some facts regarding pharmacology during the COVID-19 situation.

Are there preventive or curative medications?

While there are hundreds of trials underway or planned, there have not yet been any results that demonstrate a specific medication can prevent or cure COVID-19.^2–4 But while no vaccine has been approved, a Phase I trial of an investigational vaccine called mRNA-1273 has recently begun in Seattle.⁵ The vaccine was administered to its first patient on March 17, and the 45 volunteers, ages 18–55, will receive two doses over six weeks,⁶ meaning it will likely be several months before approval and significant manufacturing and distribution.

Lopinavir/ritonavir (Kaletra)

Lopinavir/ritonavir is an antiviral medication used to treat HIV. It has been studied as having in-vitro activity against SARS-CoV, the virus that causes SARS in humans, which is similar to the virus that causes COVID-19. While there were early hopes it could be effective for patients with COVID-19, a trial published March 18 in the New England Journal of Medicine showed it was ineffective in hastening recovery. The authors also noted the drug had no effect on viral loads in the treatment group.^7,8 At this time it does not appear lopinavir/ritonavir has a place in the treatment of COVID-19, although further research is warranted.⁹

Remdesivir

Remdesivir is an investigational nucleotide analog with broad-spectrum antiviral activity that is not approved anywhere for any use.¹⁰ Preliminary data suggest it may have activity against COVID-19, and there are multiple clinical trials in process to investigate.

Gilead also provides remdesivir on a limited basis through compassionate use, which is assessed on an individual basis and requires the patient be “hospitalized with confirmed COVID-19 infection with significant clinical manifestations.”¹⁰

A New England Journal of Medicine article published in April reported clinical improvement was seen in 68% of COVID-19 patients treated with remdesivir;¹¹ however, the study had no control group and many sources of bias.¹²

Recently the World Health Organization inadvertently published a draft (soon taken down) of an unreviewed manuscript that did not appear to show any conclusive benefit from remdesivir.^13,14

A recently published article in The Lancet describes the first randomized double-blind, placebo-controlled clinical trial assessing remdesivir use in patients with COVID-19. While there was a numerical reduction in time to improvement with remdesivir, there was no statistically significant difference when compared to placebo.¹⁵

Chloroquine and hydroxycholoroquine

While chloroquine and its derivative, hydroxychloroquine, are often used to treat malaria, rheumatoid arthritis, and lupus, it has been suggested they may be candidates to treat COVID-19 based on chloroquine’s in-vitro activity against the virus.¹⁶

On March 19 several news outlets reported President Donald Trump had indicated his administration was working with the FDA to “slash red tape” to make hydroxychloroquine immediately available, with one article saying it had been approved by the FDA.^17,18 However, other outlets reported the FDA had downplayed Trump’s statements, which had implied the process of clinical trials to assess safety and efficacy would be circumvented, stating that hydroxychloroquine was not yet approved for COVID-19 treatment.^19,20

At this time these treatments are not yet considered to be safe and effective by the FDA.

Should ibuprofen be avoided?

This question seems to have originated in a letter to the editors of The Lancet, where the authors noted that “human pathogenic coronaviruses…bind to their target cells through angiotensin-converting enzyme 2 (ACE2)” and then comment that ACE2 can also be increased by ibuprofen.²¹ The French health minister then tweeted a warning against using nonsteroidal anti-inflammatory drugs (NSAIDs), and the French health ministry instructed patients to take acetaminophen instead.²² This statement was then countered by the European Medicines Agency and World Health Organization, as well as the FDA’s official statement.^22,23 The FDA advises patients that there are other medications available over the counter for pain and fever and suggests speaking to a health professional for advice.

Should angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin receptor blockers (ARB) be avoided?

As with ibuprofen, ACE inhibitors and ARBs were highlighted as a concern in the aforementioned letter to The Lancet.²¹ These statements later spread to social media and were widely shared, leading to concerns from uninformed patients. On March 13 the European Society of Cardiology (ESC) Council on Hypertension issued a response saying there is a “lack of any evidence supporting harmful effect of ACE-i and ARB in the context of the pandemic COVID-19 outbreak.”²⁴ This was followed by a joint statement from the American Heart Association, Heart Failure Society of America, and American College of Cardiology that affirmed the ESC’s position.

Fraudulent claims

The FDA and FTC have sent warning letters to seven companies that have made fraudulent claims regarding their products’ abilities to treat or prevent COVID-19. These products include silver, essential oils, and proprietary remedies.²⁵

Conclusion

At this time the spread of COVID-19 is only beginning to reveal its impact on our global economies, societies, and healthcare systems. While the rapid spread of knowledge and information is vital to combating this pandemic, the distribution of misinformation is harmful and damaging. Caregivers, especially those on the front lines, should be knowledgeable and prepared to answer questions regarding pharmacologic treatment options for COVID-19. I encourage EMS personnel to remember that emergency medicine pharmacists are an available resource for drug information and to use them.

References

1. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19), Cases in the U.S., www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html.

2. World Health Organization. Coronavirus disease (COVID-19) Pandemic, www.who.int/emergencies/diseases/novel-coronavirus-2019.

3. U.S. Food and Drug Administration. Coronavirus Disease 2019 (COVID-19), www.fda.gov/emergency-preparedness-and-response/counterterrorism-and-emerging-threats/coronavirus-disease-2019-covid-19.

4. Centers for Disease Control and Prevention. Clinical Questions about COVID-19: Questions and Answers, www.cdc.gov/coronavirus/2019-ncov/hcp/faq.html.

5. National Institutes of Health. NIH clinical trial of investigational vaccine for COVID-19 begins, www.nih.gov/news-events/news-releases/nih-clinical-trial-investigational-vaccine-covid-19-begins.

6. O’Kane C. First patients injected with potential COVID-19 vaccine in clinical trial. CBS News, www.cbsnews.com/news/coronavirus-vaccine-jennifer-haller-seattle-first-patient-injected-with-covid-19-shot-in-clinical-trial-cure/.

7. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med, 2020 Mar 18.

8. Baden LR, Rubin EJ. Covid-19—The Search for Effective Therapy. N Engl J Med, 2020 Mar 18.

9. Hu D. LOTUS China. The Bottom Line, www.thebottomline.org.uk/summaries/lotus-china/.

10. Gilead. Gilead Sciences Update On The Company’s Ongoing Response To COVID-19. gilead.com/purpose/advancing-global-health/covid-19.

11. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med, 2020 Apr 10.

12. Farkas J. PulmCrit—Eleven reasons the NEJM paper on remdesivir reveals nothing. PulmCrit, https://emcrit.org/pulmcrit/pulmcrit-eleven-reasons-the-nejm-paper-on-remdesivir-reveals-nothing/.

13. Silverman E, Feuerstein A, Herper M. New data on Gilead’s remdesivir, released by accident, show no benefit for coronavirus patients. Company still sees reason for hope. STAT News, www.statnews.com/2020/04/23/data-on-gileads-remdesivir-released-by-accident-show-no-benefit-for-coronavirus-patients/.

14. Pham S, Goodwin J. Global stocks falter as investors lose faith in potential coronavirus treatment. CNN, www.cnn.com/2020/04/24/investing/global-stocks/index.html.

15. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet, 2020 Apr 29; www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext.

16. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov, 2020; 6(16).

17. Georgiou A. What is Hydroxychloroquine? Donald Trump Say Malaria Drug for Coronavirus Has Been Approved By FDA. Newsweek, www.newsweek.com/hydroxychloroquine-malaria-drug-coronavirus-fda-1493293.

18. Voytko L. Updated: Trump Says FDA Approved Anti-Malaria Drug Chloroquine To Test As Coronavirus Treatment. Forbes, www.forbes.com/sites/lisettevoytko/2020/03/19/trump-says-fda-approved-anti-malaria-drug-chloroquine-to-test-as-coronavirus-treatment/#c5ec42e303d9.

19. Edney A. Trump Touts Drug That FDA Says Isn’t Yet Approved for Virus. Bloomberg, www.bloomberg.com/news/articles/2020-03-19/trump-touts-malaria-drug-as-potential-coronavirus-treatment.

20. Lee A. New Details: Trump announces ‘immediately available’ drug, but experts dispute that. Atlanta Journal-Constitution, www.ajc.com/news/breaking-trump-announces-new-vaccine-treat-coronavirus/UlmcYjEZPwBxXleD74S52K/.

21. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir, 2020; 2,600(20): 30,116.

22. Godoy M. Concerned About Taking Ibuprofen For Coronavirus Symptoms? Here’s What Experts Say. NPR, www.npr.org/sections/health-shots/2020/03/18/818026613/advice-from-france-to-avoid-ibuprofen-for-covid-19-leaves-experts-baffled.

23. U.S. Food and Drug Administration. FDA advises patients on use of non-steroidal anti-inflammatory drugs (NSAIDs) for COVID-19, www.fda.gov/drugs/drug-safety-and-availability/fda-advises-patients-use-non-steroidal-anti-inflammatory-drugs-nsaids-covid-19.

24. de Simone G. Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers. European Society of Cardiology Council on Hypertension, www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang.

25. U.S. Food and Drug Administration. Coronavirus Update: FDA and FTC Warn Seven Companies Selling Fraudulent Products that Claim to Treat or Prevent COVID-19, www.fda.gov/news-events/press-announcements/coronavirus-update-fda-and-ftc-warn-seven-companies-selling-fraudulent-products-claim-treat-or.

Daniel Hu, PharmD, BCCCP, has Doctor of Pharmacy degree and is a critical care and emergency medicine pharmacist. He is a frequent speaker at conferences and has many publications in peer-reviewed journals.