The Coronavirus: Potential Treatments and Drugs to Potentially Avoid

Pharmacology and SARS-CoV-2

I have taught pharmacology, the science of drugs, going on thirty years. Several matters related to pharmacology have appeared regarding SARS-CoV-2. I will address two broad questions. First: do some drugs work against the virus? Second: do some drugs make the infection worse?



Let's start off with some perspective. All of this is new. Even a quick study rushed to publication takes months: and we are not many months into this infection. There is no definitive statement regarding any of these matters, just a handful of very recent publications along with too many anecdotal reports. In the early days of AIDS (of which I have some familiarity), a lot of the original information about treatment candidates proved to be born out of desperation rather than usefulness.

Coronaviruses, along with rhinoviruses and adenoviruses, are among those that cause the common cold. That's the bad news: common colds are common. They are readily transmissible and, as we all know, there is no cure for the common cold. Beyond that, SARS-CoV-2 is much more dangerous than a typical cold or flu.

On the other hand, treating the SARS-CoV-2 virus is not the same as curing the common cold. We are not targeting all of the potential "cold" viruses here: just one. That provides hope for vaccines, and perhaps, pharmaceutical agents. (Strictly speaking, vaccines are pharmaceutical agents, but for the sake of this piece, I'll only be talking about non-vaccine drugs.) Some of the drugs mentioned here were tested during previous SARS outbreak.

Potential Drugs to Treat Coronavirus

These are some of the drugs that have been put forward as to helping with COV-19 infection.

Oseltamivir (Tamiflu). This drug is taken orally to help curtail influenza disease course. It is useful only if the drug is taken within the first two days of symptoms. Even then, it will only briefly shorten the recovery time. Oseltamivir helps prevent newly-formed viral particles from escaping an infected cell and therefore infecting new cells. It does this by inhibiting the neuraminidase enzyme. It is available orally and that's probably why it is prescribed a lot: convenience. In contrast, zanamivir (Relenza) is an inhalant that also inhibits neuraminidase used for flu. It has less side effects than oseltamivir because it is an inhalant: less gets to the blood, more hangs around the lungs where it is needed. Perhaps the best thing about oseltamivir is that it can be used for prophylaxis of the flu, which is especially helpful in high intensity infection settings such as nursing homes.

I've never been a big fan of oseltamivir. Its window of use is brief, its maximum effect is limited, and its side effects are potentially problematic. When I was hospitalized for bacterial pneumonia I was started on oseltamivir -- six days after arrival. That made no sense to me unless there was a concern I was coming down with a secondary infection. I experienced hallucinations. I can't be sure it was the oseltamivir, but delirium is one of its side effects.

Oseltamivir has not been shown to be effective in the previous SARS outbreak, nor did it change long-term outcomes of previously infected SARS patients. It is unlikely that it will work for the current coronavirus.

Favipiravir (Avigan) is fascinating. It has been shown to have efficacy for a variety of RNA-viruses. It has been approved for use in China, Japan, and Italy and has made it through a pair of Phase 3 studies in the US for the treatment of influenza. (China and Italy approved it just this past week.) Its mechanism of action is similar to that of ribavirin and remdesivir (below): they all inhibit RNA virus RNA polymerase.

On March 17, China announced that they had completed clinical studies for favipiravir and that it was helpful in recovery from the disease. To quote:

"The Third People's Hospital of Shenzhen in Guangdong province conducted a clinical trial on 80 patients, with 35 receiving the drug. The results have shown patients treated with favipiravir took four days before being tested negative, whereas the control group took 11 days."

That's a pretty dramatic difference. It is said to not be helpful in severe disease. As I discussed in my pharmacology class, with severe viral diseases such as influenza, all the cells that are going to be infected are infected.

I am surprised by their description of "no obvious adverse effects," same source as above, however, Phase 2 trials in the US showed a low degree of side effects.

Phase 3 studies against influenza virus were finished in 2015. No results have been presented. That suggests the results were not good, at least against the flu virus. Good results get published and the drug is put in for approval.

Remdesivir is much like favipiravir, only earlier in being studied. It has the same mechanism of action. Studies are beginning now.

Lopinavir/ritonavir (Kaletra in combination). These are anti-HIV protease inhibitors. There is no reason to believe they should work on coronavirus and an initial study indicates that they don't.

Chloroquine (Araclen) and hydroxychloroquine are classical antimalarial drugs. For decades chloroquine was the drug of choice against malaria due to being effective while being safer than the others. Now chloroquine-resistant malaria dominates the world and, we have some newer choices that are more powerful, the artemisinins. Hydroxychloroquine is also an antiinflammatory and is used for rheumatoid arthritis.

When I said these are safer than other antimalarials, I didn't mean that they don't have any toxicities. Like quinine, chloroquine and hydroxychloroquine can affect blood sugar. It can cause headaches, diarrhea, and hemolytic anemia in patients with G-6-PD deficiency.

There has been one smallish study that found that azithromycin (an antibacterial protein synthesis inhibitor, Zithromax) and hydroxychloroquine helped to dramatically reduce the length the patient carried the virus and the amount of the virus. The drop out rate was high (6 out of 26) among those initially treated with three of those going to the ICU and one dying. All in all, the study is open for interpretation as either hopeful or problematic. As is usually the case, more studies are needed.

Another study from China found efficacy from chloroquine and remdesivir, in vitro. 

So how does chloroquine or hydroxychloroquine help? That's unknown. Perhaps it is the anti-inflammatory effect. The azithromycin might be preventing secondary bacterial pneumonia infection or it might be due antiviral properties that azithromycin is claimed to have. Furthermore, azithromycin is also an antiinflammatory. On the other hand, since chloroquine has been shown to be effective in vitro, that suggests its effect is more than the antiinflammatory actions.

Concerns about what drugs not to use.

ACE inhibitors / Angiotensin Receptor Blockers (ARBs)

These drugs are standard care for high blood pressure and are used as adjuncts in congestive heart failure. Do they make coronavirus symptoms worse? There are three reasons why this is suspected.

1) SARS-CoV-2 uses the angiotensin coverting enzyme type-2 as a cell receptor for infection.
2) ACE inhibitors, in particular, have been shown to upregulate angiotensin converting enzyme. 
3) Among the co-morbidities for death in Italy in one study, 74% of patients had high blood pressure. This might simply be because high blood pressure and age have a strong association. Age also presents a strong association with SARS-CoV-2 lethality.

In a recent commentary, it was strongly suggested that patients do not stop using these popular blood pressure medicines: the evidence for bad outcome with SARS-CoV-2 infection is not clear. The authors disclosed pharmaceutical ties. Nevertheless, the advice is generally sound.

Ibuprofen / NSAIDs / Acetaminophen.

Ibuprofen in particular was mentioned as something that might be avoided. The director of the National Institute of Allergy and Infectious Diseases, Anthony Fauci, suggests that this is an alarmist extrapolation from aspirin in viral infections causing Reyes' syndrome in children. Others have suggested that fever has a place in the body's fight against infections, and that NSAIDs and acetaminophen lower fever.

Let's take these one by one. The Reyes' concerns should not carry over to other NSAIDs and should not affect decisions in adults. For children, for pain and fever, it is generally recommended to avoid aspirin. Some physicians recommend acetaminophen. Acetaminophen overdose is so common, I would go with a non-aspirin NSAID.

Is lowering the fever in the case of a viral infection a bad strategy? Is the body fighting the infection with fever? In the case of bacterial infections this makes more sense to me. When culturing human pathogenic bacteria, the classic temperature of the heating device is 98.6 F (37 C). This concept to  doesn't pass over to viruses. Viruses in the blood are not going to affected by a fever. Viruses perform their main functions, including replication inside of cells, which I suspect are less susceptible to overall body temperature changes. That said, there is an argument that the induction of heat-shock proteins is protective. In the cited study, the temperature was raised to 40 C (104 F), which is a fairly heavy duty fever, the upper range below emergency.

Asthmatics are advised to avoid NSAIDs. This is because NSAIDs block the production of prostaglandins and the action of blocking the production of prostaglandins shunts the precursors over to leukotrienes, some of which mediate inflammation, and, in particular, mediate inflammation in asthma. If those leukotrienes are exacerbating symptoms in coronavirus patients with compromised respiration, this may be a concern. Of course, some asthma patients will have coronavirus. Perhaps using a leukotriene synthesis blocker such as zileuton could be helpful to overcome this.

The FDA is stating that there is not enough evidence to exclude the use of NSAIDS in coronavirus.

So, what's the bottom line? This is my take. If you have mild symptoms of fever and aches and you don't know if you have coronavirus, and you are over 12 years of age and don't have asthma, take an aspirin or other NSAID. The most significant exception to that rule is if you are allergic to aspirin. In the same situation if you're under 12, then try acetaminophen or ibuprofen. If you have coronavirus and you are not actively have problems breathing, then the NSAIDs are okay. For asthma, acetaminophen will not cause the problems with peripheral leukotrienes.

NSAIDs may be contraindicated if the infection is severe and with active respiratory problems. Even then, the evidence is out.

My primary sources in putting this together were (a) Anthony Fauci's March 18 podcast with the editor of the Journal of the American Medical Association, and (b) Derek Lowe's In the Pipeline blog as part of Science Translational Medicine, his March 6th and (c) March 19th entries.

(a) https://youtu.be/EXY76TKNy2Y
(b) https://blogs.sciencemag.org/pipeline/archives/2020/03/06/covid-19-small-molecule-therapies-reviewed
(c) https://blogs.sciencemag.org/pipeline/archives/2020/03/19/coronavirus-some-clinical-trial-data

Continue reading →

A Mystery Writer's Guide to Drugs and Poisons. Part One.

I have a doctorate in Pharmacology--the science behind drugs--and have taught the subject to medical students for twenty years. I have also taught Toxicology, the science of poisons. The two subjects overlap. As any pharmacologist can tell you, every drug can be a toxin, it just depends on the dose.

Drugs and Poisons.

Drugs and/or poisons take their place in mystery literature as murder weapons, as addictive substances related to character flaws or criminal ventures and, in thrillers, as potential terrorist threats which can wipe out whole cities.

On a less dramatic note, characters use drugs for their various ailments and may suffer from their side effects and it is important to get the details right.

Pharmacology and Toxicology are vast subjects with issues related to the thousands of drugs and poisons. In this series I will try to deal with some of the most common situations the mystery writer may encounter. First, however, some basics on how drugs and toxins work.

What Makes Drugs and Toxins Work.

The human body is run by chemicals that it produces. These can be hormones that are released by glands which act elsewhere in the body on organs and tissues or else they can be locally acting substances such as neurotransmitters. What's a neurotransmitter? Nerves, both those that run like wires around the body, and those that comprise the brain, act by releasing stimulants and depressants which affect tissues or act at another nerve. These chemicals are neurotransmitters and run the communication system of the body, giving orders to both the automatic systems that govern functions such as breathing and digestion and the voluntary system that controls movement and willful actions. Neurotransmitters also control the brain functions: consciousness, memory, wakefulness, euphoria, etc.

So, what does a drug do? In most cases* it either acts like the natural chemical or blocks the effect of the natural chemical at its site of action.

Let's have a couple of examples. You are probably familiar with adrenaline (also called epinephrine). It is a chemical released by the body in response to stress or danger. Among other actions, it opens up the lungs for breathing, it makes the heart beat faster, it raises the blood pressure and it directs blood flow to the skeletal muscles. The set of effects from adrenaline are often described as preparing you for "fight or flight."

Adrenaline can be given as a drug. Shock involves a precipitous drop in blood pressure. A doctor may want to raise blood pressure using adrenaline in the case of anaphylactic shock (the type of shock that occurs with a severe allergic reaction such as bee-sting allergies).

Adrenaline was formerly given for asthmatic attacks: it relaxes the bronchiole muscles of the lungs to make breathing easier. In this case, we get to a toxicity: adrenaline not only opens up the bronchioles, it causes the heart to race. It can cause death in those prone to heart attacks. As a general principle of toxicity, some people are more susceptible than others. There are other drugs which can be used for asthma that do not have this effect.

To get back to what I noted above, some drugs mimic while other block the effects of natural compounds. Instead of raising the blood pressure with adrenaline, you might want to lower the blood pressure by providing a drug that blocks the action of circulating adrenaline (and its companion which is released by nerve endings, noradrenaline). Such drugs are often called blockers or inhibitors or else by the more technical term, antagonists.

How Do Drugs Achieve Their Effect?

Drugs, and their natural chemical counterparts, work by binding to receptors which turn on or off cell processes. What is a receptor? The following analogy is over a century old. A drug is the key, the receptor is the lock (or ignition switch). The receptor is typically on the outside of a cell. The drug is carried by blood to the outside of the cells where the drug turns on the cells causing a tissue effect. Why a particular tissue? That's where the receptors are which fit the keys: adrenaline on the heart tissue (and blood vessels and elsewhere where it has its actions).

Let's look at another example. Acetylcholine is a neurotransmitter with many effects throughout the body. Nerves which go to the skin release acetylcholine causing a person to sweat. Nerves which go the salivary glands release acetylcholine causing a person to salivate.

Acetylcholine is also released at the nerves which connect the brain to the skeletal muscles. The skeletal muscles are those that control voluntary movement. Drugs that act like acetylcholine are given to patient with myasthenia gravis. Why? Myasthenia gravis is a disease in which a person's immune system attacks the acetylcholine receptors on the outside of skeletal muscles. The person thereby loses muscle strength. By acting like acetylcholine, a drug can activate some of the remaining receptors.

However, in other circumstances you might want to give a drug that blocks acetylcholine at the skeletal muscles. Why would you want to do that? These drugs (skeletal muscle blockers) are given prior to surgery to prevent the patient from flinching. (General anesthesia does not paralyze the patient, anymore than sleep does not paralyze us.) A good plot device: a murderer substitutes or cuts off the skeletal muscle blocker being infused during a delicate life-or-death surgical procedure.

Let's look at the skeletal muscle blockers from the point of view of poisons. Tubocurarine (Curare) paralyzes the muscles and was discovered by a researcher who noted South American tribes using poison-tipped blow darts to capture animals. It can be fatal in animals or humans because one set of skeletal muscles helps us to breathe. (During surgery, the patient is placed on mechanical ventilation.)

After curare was discovered, but well before it was purified well enough from its plant source to be used as a drug, it made for a popular poison in mystery stories. No one interested in murder cares whether a poison is pure enough to avoid additional toxic effects.

Another set of toxins work through the acetylcholine system. Popular as the villainous weapons in thrillers and popular with villains in real life (Saddam Hussein, the Tokyo attacks), the nerve gases first overload and then knock out the acetylcholine receptors. The effects are several fold. First you have the twitching and spasms from having the skeletal muscles activated. You have the sweat glands and salivary glands turned on. Then you have the skeletal muscles shut down, including those that help you breathe. The nerve gases make for the more terrifying sort of poisons in part because they are active in small concentrations, they can be absorbed by breathing and through the skin (not many toxins can), and they can be spread in a suspended gaseous form. They also make for great plot devices because they have specific antidotes—and not many poisons do.

The Differences Between Drugs and the Natural Body Chemicals.

Although human-made compounds such as adrenaline can be used as drugs, a general rule is that the body exquisitely regulates its own compounds, producing them as needed and then quickly stopping the effect. One of the main ways in which the body stops the action is by breaking down the chemical into ineffective parts (metabolites). Adrenaline has a half-life of about 2 to 3 minutes. Acetylcholine, at the nerve ending, has a half-life of seconds. One major difference between synthesized drugs and the natural compounds is that the synthesized drugs act for a longer time. For example, an asthmatic patient might be taking a drug that acts like adrenaline in the lungs but has a half-life of hours.

So what is half-life? Unless the drug (or toxin) overwhelms the body's system of elimination, the body will eliminate half of the drug dose in a given period of time. A simple illustration is this:

Digoxin (for heart failure or arrhythmias). Half-life: 40 hours.

• Concentration in blood. (micrograms per milliliter)

• Zero hour. First measure: 8 ug/mL
• 40 hours later: 4 ug/mL
• 40 more hours later: 2 ug/mL
• 40 more hours later: 1 ug/mL

The drug is disappearing by halves, moving like the traveler on Zeno's bridge.

I provide this table to overcome a misconception. Half-life is not how long a drug acts. It may still be acting the level of 1 ug/mL. -- Or else it may not, it may be at a concentration that is no longer causing an effect. Half-life describes the elimination of the drug. The elimination of its effect is determined by the lower threshold of its effective concentration.

Extending This To Other Drugs.

There are thousands of drugs belonging to hundreds of systems. The differences between them is what receptors they act on, individual toxicities, half-lives, and routes of administration. 

For example, morphine-related drugs act through receptors which are naturally activated by the endorphins. These receptors are located in places which cause pain relief, euphoria, depressed breathing (the main fatal effect with an overdose), and constipation (the common problematic side effect). These receptors are present in other places to provide minor effects such as pinpoint pupils.

Morphine-blockers such as naloxone (Narcan) block the receptors. This won't make much of a difference (they are blocking pain-relief rather than causing pain) unless someone has a dose of morphine-related drugs or endorphins present. In such a case the drug wipes out the euphoria, pain-relief, etc. and restores the breathing.


*A final note on this part. Does every drug either mimic or block the action of a natural human substance? No. One alternative mechanism of action comes with the antibiotics which interfere with the chemistry of microorganisms.

Next. Some Differences Between Drugs and Toxins.

Never Kill A Friend, Ransom Note Press

Never Kill A Friend is available for purchase in hard cover format and as an ebook.
The story follows Shelley Krieg, an African-American detective for the Washington DC Metro PD as she tries to undo a wrong which sent an innocent teenager to prison.

Hard cover: Amazon US
Kindle: Amazon US
Hard cover: Amazon UK
Kindle: Amazon UK
Barnes and Noble  

Continue reading →