Metabolism and excretion of some common medications used in COVID-19, heart disease and diabetes.
Usage of supplements has increased dramatically this last decade. From herbs to vitamins and mineral, consumers are interested in improving health, self-treatment and preventing diseases. Often using information from the internet to self-prescribe, many consumers believe that natural products are safe, while many others avoid using these products because of the lack of an approval process by health officials in many countries. Herbs and other supplements including proteins, vitamins and minerals provide significant benefits to health. The lack of guidance from health professionals however can be problematic. When combined with drugs and disease, herbs can interact and cause side effects. Some of the steps to evaluate the safe use of supplements is to know their mechanism of action, clinical effect, and consumers’ medical history. For example, an herb that induces liver enzymes will reduce the effect of a drug that is metabolized by these same enzymes. This can be life threating if the patient depends on this drug for normal function. Based on drug-herb interaction experience and literature review, this book chapter provides insights into safe use of echinacea, licorice, turmeric, and black seed in patients with heart disease, diabetes, and COVID-19.
- drug-herb interaction
- heart disease
Dietary supplements are defined in the United States as products that contain one or more dietary ingredient such as vitamins, minerals, herbs, botanicals, and amino acids and are intended to supplement the diet . In other countries dietary supplements are named differently including natural health products, complementary medicines, food supplements, and others . Nonetheless, “dietary supplements” is a general term for products that mostly contain herbs, botanicals, proteins, and/or vitamins and minerals that are used with the intention to promote health. Despite the legal framework, dietary ingredients are often used and recommended for treating or preventing diseases. In this chapter, “dietary supplements” will be used as a general term to encompass several dietary ingredients.
Usage of dietary supplements has increased this last two decades . From herbs, proteins, to vitamins and minerals, consumers are interested in self-treatment and preventing diseases . Often using information from the internet to self-prescribe, many consumers believe that natural products are safe, while many others avoid using these products because of the lack of an approval process by health officials in many countries. Many dietary supplements provide significant benefits to health . However, the lack of guidance from health professionals can be problematic.
Dietary supplements are likely safe when used as prescribed [4, 5]. But, when combined with drugs and disease, these products can interact and cause side effects [6, 7]. Some of the steps to evaluate the safe use of dietary ingredients is to know their mechanism of action, clinical effect, and consumers’ medical history. For example, an ingredient that induces liver enzymes will reduce the effect of a drug that is metabolized by these same enzymes. This can be life threating if the patient depends on this drug for normal function.
Due to the benefits that several of these dietary ingredients provide, it is important to evaluate their safety for wide spread recommendation. Particularly due to times of pandemic such as the coronavirus disease 2019 (COVID-19) , ways to prevent disease severity and to be used as adjunct treatments are needed. Several dietary ingredients have been reported to be effective against COVID-19 in review articles. For this book chapter, 30 review articles and meta-analysis were evaluated for the selection of the dietary ingredients herein discussed. The selection criterium was based on the number of articles that cited the ingredients as being effective as well as the commonality and accessibility of the ingredients across the globe. Vitamins and minerals were excluded due to their safety being extensively researched. Because COVID-19 severity is worse among patients with diabetes and cardiovascular disease, the safety use of these ingredients in the context of these comorbidities are presented here.
2. Comorbidities and their drug treatments
COVID-19 is a respiratory infection caused by the virus named “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) . COVID-19 is a novel disease officially declared as a pandemic on March 11th, 2020 [9, 10]. SARS-CoV-2 has infected 98.2 million people worldwide and caused 2.1 million deaths as of January 24th, 2021 . COVID-19 is characterized by dry cough, fever, and fatigue symptoms in adults while in children rhinorrhea, abdominal pain, and diarrhea are also present . SARS-CoV-2 binds directly to angiotensin converting enzyme 2 (ACE2) for subsequent entry into cells [10, 12]. Infected cells respond to the virus by generating pro-inflammatory cytokines and chemokines that sometimes lead to a cytokine storm which aggravates the disease [10, 12, 13]. Those with certain underlying health conditions such as respiratory disease, cardiovascular disease, and diabetes as well as older individuals seem to be at a higher risk for developing severe complications from the infection [14, 15]. Because SARS-CoV-2 has approximately 80% genomic homology with SARS-CoV-1, the virus that caused the 2002–2003 epidemic, many research studies have proposed the use of treatments that were effective against SARS-CoV-1 . Current treatments for COVID-19 used in the clinics are ACE2 inhibitors, corticosteroids, chloroquine, anti-inflammatory tocilizumab, comostat, protease inhibitors (lopivavir and ritonavir), and RNA polymerase inhibitors (remdesivir, favipiravir) . Some of the established protocols are: no treatment for mild cases besides acetaminophen for fever; hydroxychloroquine + azithromycin for moderate cases; tocilizumab or sarilumab for worsening respiratory function; and remdesivir, convalescent plasma, corticosteroids for respiratory failure. NSAIDs such as ibuprofen are not recommended due to potential increase in ACE2 expression . Lastly, it has been suggested that reduction in cholesterol decreases viral mRNA . Thus, treatments that reduce cholesterol in addition to antivirals, anti-inflammatories, and respiratory support should be beneficial in managing COVID-19.
2.2 Heart disease and diabetes
As noted above, patients with heart disease and diabetes are more likely to develop severe COVID-19. Thus, many of these patients will be given medications for COVID-19 on top of the current heart/diabetes medications they take. For example, patients continue to take ACE inhibitors or angiotensin II receptor blockers (ARBs) during COVID-19 infection . Furthermore, these are the patients more likely to benefit from dietary ingredients that assist in preventing or treating COVID-19. Due to multiple treatments at once, the likelihood of drug–drug and drug-herb interaction in these patients is high. Drug treatments for heart disease include several types: anticoagulants, antiplatelets, ACE inhibitors, ARBs, beta blockers, calcium channel blockers, cholesterol lowering, diuretics, and vasodilators . For diabetes main medication classes include sulfonylureas, meglitinides, metformin, and glitazones . The metabolism of some commonly prescribed of these medications are listed in Table 1. As noted, the most common cytochrome P450 enzyme involved in the metabolism of these drugs are CYP3A4, followed by CYP2C9, 2D6, and 2C8 [21, 22, 23, 24, 25]. Approximately half of them are primarily excreted via the kidneys.
|Drug categories||Liver metabolism||Renal excretion||References|
|ACE inhibitors:||[21, 22]|
|Hydroxychloroquine||Partially metabolized||Slowly excreted by the kidneys|||
|Protease inhibitor, ritonavir||CYP3A4 and 2D6 inhibitor||Minimal renal excretion||[16, 23]|
|RNA polymerase inhibitor, remdesivir||CES1 to form active metabolite||~50% renal excretion|||
|Antiplatelet, clopidogrel||CYP 2C19 forms active metabolite||~50% excreted in urine|||
|Beta blocker, atenolol||Minimal metabolism||Major renal excretion|||
|Cholesterol lowering:||[22, 25]|
|Diuretic, spironolactone||Extensive metabolized||Major renal excretion|||
|Sulfonylureas||[21, 22, 25]|
|Meglitinides, repaglinide||Metabolized by CYP3A4||Minimal renal excretion|||
|Metformin||Minimal metabolism||~90% renal excretion|||
|Glitazones, pioglitazone||Metabolized by CYP2C8||~15–30% renal excretion|||
Echinaceaspp. (echinacea) – Antiviral and immune support
3.1 Echinacea in COVID-19
Echinacea has antiviral and immunomodulatory effects that seems to be promising against COVID-19 [13, 26]. Several studies have investigated the benefits of echinacea in treating and preventing respiratory tract infections such as the common cold, but not for other health purposes . No studies have yet been completed on echinacea and COVID-19 . A meta-analysis including 17 clinical trials found that echinacea is safe and effective in preventing or treating viral infections. In a separate analysis including 12 clinical trials, echinacea showed to decrease or not change pro-inflammatory cytokines associated with cytokine storm (IL-6, IL-1β, and TNF-α) and increase or not change anti-inflammatory or immune-stimulatory cytokines (IL-10, IL-2, IL-8, IL-3, and IFN-γ). These effects are beneficial during infections since immune stimulatory and anti-inflammatory effects are needed but pro-inflammatory cytokines can aggravate the disease. Adverse events were mild with the most common reported being insomnia, gastrointestinal, and anxiety. One case of serious erythema was reported. Most studies included healthy participants and echinacea dose and method of extraction were quite variable making it difficult to evaluate safety in patients with comorbidities .
3.2 Echinacea in diabetes
Not many studies have investigated the effects of echinacea in diabetes. In Wistar rats, 33 days of echinacea root extract showed hypoglycemic activity similar to glibenclamide. No safety parameters were investigated .
3.3 Echinacea in heart disease
Almost no studies have evaluated the effects of echinacea on heart conditions such as hypertension and hypercholesterolemia. In one study with 374 elderly, 349 reported to use over-the-counter drugs and 43 reported to use herbal medicine. Echinacea was the most common herbal therapy used while aspirin, acetaminophen, laxatives, antiacids, and vitamins were the most common over-the-counter drugs . This single study suggests the potential for interaction of echinacea with drugs.
3.4 Echinacea toxicity
In a review article, echinacea was considered to have a high or medium evidence for efficacy and safety . Debatable concern of hepatotoxicity with echinacea when used for more than 8 weeks has been raised . On the other hand, echinacea has shown hepatic and renal protection against toxins in rats with no effect by itself on liver and kidney parameters including AST, ALT, ALP, blood urea nitrogen and creatinine . No toxicity was found in rats and mice after oral or intravenous injection of
3.5 Echinacea pharmacokinetics
In vivo pharmacokinetics in 12 healthy men and women,
3.6 Echinacea safety summary
Echinacea is likely safe when taken short-term, up to 8 weeks, in healthy adults. Unknown safety in patients with diabetes or heart disease. Caution should be taken when combining with medications metabolized by CYP3A, 1A2, and 2C9 enzymes.
Glycyrrhiza sp.root (licorice) – Antiviral and respiratory support
4.1 Licorice in COVID-19
Licorice root is used as a flavoring agent in food in many countries. In the United States, anise oil is often used for this purpose. Licorice is promoted as a dietary supplement for digestion, cough, infections, and others . Frequently recommended by herbalists, licorice has recently shown to be the herb most frequently used for COVID-19 treatment [41, 42]. Several review articles have discussed the potential effectiveness of licorice in treating COVID-19 for its antiviral, anti-inflammatory, spasmolytic, and expectorant effects [9, 10, 12, 13, 14]. Some in vitro studies showed that the active component glycyrrhizin inhibits the replication of SARS-coronavirus (SARS-CoV) [43, 44]. Other in vitro studies showed that glycyrrhizin may prevent SARS-CoV-2 entry by binding to ACE2 receptors and other protein targets [45, 46]. Clinical trials of licorice use during COVID-19 are ongoing. Daily doses range from 250 mg 25% extract (62.5 mg glycyrrhizin) for 10 days to 2.28 g 3% extract (70 mg glycyrrhizin) for 7 days [47, 48].
4.2 Licorice in diabetes
Not many studies have investigated the effects of licorice in diabetes. In a clinical trial with 58 overweight and obese but otherwise healthy volunteers, 1.5 g licorice extract (<0.01% glycyrrhizin) for 8 weeks decreased insulin and HOMA-IR without side effects . In cell cultures, de-glycyrrhizinated or regular licorice showed to be a potential therapeutic target in diabetic nephropathy . In diabetic mice, licorice hydrophobic flavonoids demonstrated abdominal fat-lowering and hypoglycemic effects .
4.3 Licorice in heart disease
Cases of hypokalemia and hypertension have been reported after daily ingestion of licorice tea or after short-term high dose [52, 53, 54]. In one case patient was combining licorice with the glucocorticoid medication fludrocortisone . The active components of licorice, glycyrrhizinates, inhibit the enzyme responsible for inactivating cortisol and bind to mineralocorticoid receptors resulting in reversible hyper-mineralocorticoid effects . A meta-analysis with 18 clinical trials found that chronic daily intake of 100 mg glycyrrhizin increases systolic and diastolic blood pressure . In another meta-analysis including 26 clinical trials and 985 subjects, mainly healthy and overweight but some with hypercholesterolemia, found licorice to reduce body weight and BMI but increase diastolic blood pressure. Licorice was given as licorice flavonoid oil with a dose range of 300 mg to 1.8 g/day for 2–16 weeks . In a dose–response relationship investigation in healthy men and women, licorice root with 108 or 217 mg of glycyrrhizin per day for 4 weeks caused no adverse events. However, licorice with 380 and 814 mg glycyrrhizin caused headache, arterial hypertension, hyperkalemia, and peripheral edema. One individual had a family history of hypertension . Lastly, a similar study compared adverse events in patients with hypertension versus normotensive individuals during 100 g licorice containing 150 mg glycyrrhetinic acid per day for 4 weeks. Systolic and diastolic blood pressure were slightly increased in normotensive (3.5 and 3.6 mmHg) but significantly greater increase in hypertensive patients (15.3 and 9.3 mmHg). Increase in urinary cortisol correlated with the rise in blood pressure . These data suggest that glycyrrhizin at dose >200 mg/day short-term and > 100 mg/day long-term in patients or healthy individuals can cause reversible hyperkalemia and hypertension.
4.4 Licorice toxicity
Despite licorice being a substance generally recognized as safe (GRAS) in the United States  and regarded as having a high safety profile because it is consumed as food , licorice can cause hypertension and hypokalemia in a dose-dependent manner . However, safe dose will vary depending on licorice’s composition and the underlying medical conditions. Those with hypertension, heart or kidney disease are more sensitive to licorice toxicity . In a study involving 360 subjects, no clinically significant change in renal function (potassium, blood urea nitrogen, and creatinine levels) were found in 98.3% of the subjects after ~19 days of ~8 g licorice per day taken as dietary supplements that contained other ingredients. The remaining 1.7% of subjects developed hyperkalemia . In a safety and toxicity study with 39 healthy female and male volunteers aged 19–40 years old, glycyrrhizic acid was administered at 1, 2, and 4 mg/kg body weight daily for 8 weeks. A no-effect level of 2 mg/kg was found and applying a 100-safety factor, the acceptable daily intake of 0.2 mg/kg body weight was proposed. This is equivalent to 12 mg glycyrrhizic acid/day for a 60-kg person . Similarly, based on review of in vivo and clinical evidence, an acceptable daily intake has been proposed to be 0.015–0.229 mg glycyrrhizin/kg body weight . The acceptable daily intake without a safety factor is equivalent to 120 mg glycyrrhizic acid. This dose could be considered safe if used short-term in a situation of high benefit versus risk.
4.5 Licorice pharmacokinetics
4.6 Licorice safety summary
A safe daily dose for short-term use consists of licorice with less than 100 mg glycyrrhizin. For daily long-term use a dose of 12 mg glycyrrhizin has been proposed. COVID-19 studies are using short-term doses of <100 mg glycyrrhizin per day. Caution should be taken when combining licorice with medications. Licorice inhibits several cytochrome P450 enzymes including CYP1A2, 2B6, 2C8, 2C9, and 2C19. Only
Curcuma longa(turmeric) – Antiviral and anti-inflammatory
5.1 Turmeric in COVID-19
Turmeric has antiviral and anti-inflammatory effects that might benefit COVID-19 patients [10, 13]. It has also been hypothesized that the antioxidant effects of turmeric benefit diabetic patients during COVID-19 infection . However, some has expressed concerns that curcumin, the main active component of turmeric, might increase the expression of ACE2 and worsen COVID-19 infection as well as increase pro-inflammatory cytokines and worsen COVID-19 in patients with cytokine storm . In the contrary, curcumin binds to viral S protein and the viral attachment sites of the ACE2 receptor protein to inhibit the entry of SARS-CoV2 [18, 68]. In addition, curcumin has shown to reduce inflammatory cytokines in COVID-19 patients. In a clinical study with 40 COVID-19 patients, curcumin given as nano-curcumin at 160 mg/day for 14 days reduced the inflammatory cytokines IL-6 and IL-1β as well as clinical manifestations (fever, cough, dyspnea, headache, chest radiography, lymphocyte, white blood cells, and platelets count) in comparison to placebo-treated group. Both groups were taking atorvastatin, bromhexine, and betaferon concomitantly with 5–15% of them having diabetes, cardiovascular disease or renal disease. These results suggest the effectiveness and safety of curcumin in COVID-19 patients with underlying medical conditions .
5.2 Turmeric in diabetes
In clinical trials with type 2 diabetic patients, curcuminoids from 250 mg/day for 9 months to 1 g/day for 3 months improved glycemic control, β-cell function, insulin resistance, and reduced inflammatory cytokines with no major adverse effects. Minor side effects included diarrhea, constipation, vertigo, and itching. Some clinical and preclinical studies also showed that curcumin improve biomarkers of liver and kidney damage . In a clinical trial on 46 patients with diabetic nephropathy, 1.5 g curcumin for 16 weeks improved 24-h urine analysis for albuminuria with no change in blood urea nitrogen, creatinine, fasting blood sugar, 2-h postprandial blood sugar, lipid profile, serum albumin, and hemoglobin A1C in comparison to placebo and baseline .
5.3 Turmeric in heart disease
A recent meta-analysis found that turmeric or curcumin have no effect on diastolic blood pressure and minor effect on systolic blood pressure when taken for longer than 12 weeks . A meta-analysis that included 7 randomized, placebo-controlled clinical trials in patients with cardiovascular risk factors (i.e., non-alcoholic fatty liver disease, metabolic syndrome, type 2 diabetes, prehypertension, and dyslipidemia) found turmeric powder at 2–2.4 g/day for 1–2 months, turmeric extract with 0.6–1.9 g curcuminoids/day for 2–6 months, or curcumin at 70–80 mg/day for 2–3 months were effective in reducing serum LDL-cholesterol and triglycerides levels. Adverse events reported were abdominal pain, nausea, dyspepsia, constipation, and hot flushes. Hot flushes were also reported in the placebo group. In 3 of the trials patients were kept on their medications during the study; however, only one trial disclosed the name of the concomitant drug treatment (metformin) .
5.4 Turmeric toxicity
Turmeric has GRAS status in the United States . Through a toxicological assessment, the European Food Safety Authority (EFSA) has recommended curcumin daily intake be ≤3 mg/kg body weight per day (180 mg/day in 60 kg individuals) . In 2–year oral feed studies, turmeric oil at 79–85% curcumin showed no biological significantly differences in hematology, clinical chemistry (liver and kidney function markers), and urinalysis parameters, but showed to potentially cause carcinogenicity in mice and rats especially in females at doses ≥100 mg/kg body weight in rats and 300 mg/kg body weight in mice . However, the EFSA concluded that curcumin is not carcinogenic and studies have demonstrated the benefits of curcumin as an adjunct treatment of cancer . High daily dose of curcumin might cause hepatotoxicity. In rats, 25 and 100 mg/kg body weight for 90 days of curcumin induced liver injury through the generation of reactive oxygen species and pro-inflammatory cytokines as well as reduced antioxidant and detoxifying enzymes SOD and GST . Similarly, 5% turmeric via diet for 90 days in female Wistar rats and 0.2% turmeric via diet in female Swiss mice was hepatotoxic. Human equivalent dose for these rodent studies ranged from 250 mg curcumin/day to 1 g–50 g turmeric/day [79, 80].
5.5 Turmeric pharmacokinetics
Turmeric constituents have shown to inhibit p-glycoprotein in vitro and in vivo models . Inhibition of p-glycoprotein can lead to increased bioavailability of drugs . Curcumin is primarily eliminated in the feces with little renal excretion in a rat study . In a pharmacokinetics study with healthy adults, turmeric reduced the bioavailability of the beta-blocker talinolol . Curcumin was safe and effective when combined with glyburide in patients with type 2 diabetes. Better cholesterol and glycemia control without hypoglycemic side effects were observed. Curcumin increased AUC but did not change Cmax of glyburide . In rats, curcumin increased the Cmax, AUC0-t and half-life of amlodipine – an antihypertensive drug . Amlodipine is metabolized by CYP3A4 in humans . Curcumin inhibits several hepatic CYP enzymes including 3A4, 1A2, 2B6 (competitive type of inhibition), 2D6 and 2C9 (non-competitive inhibition) in human recombinant cytochrome P450s . However, it is been suggested that these effects are not clinically significant due to poor bioavailability of curcumin. In fact, in a pharmacokinetics study in healthy volunteers, 4 g curcuminoids +24 mg piperine to enhance bioavailability did not affect Cmax, AUC, clearance, or half-life of drugs metabolized by CYP3A, CYP2C9, and UGT, SULT conjugation enzymes .
5.6 Turmeric safety summary
Turmeric is safe and effective at doses ≤250 mg curcumin/day. Higher doses are associated with hepatotoxicity and potentially carcinogenicity. Doses as low as 70–250 mg curcuminoids/day has shown to be effective in metabolic disorders and COVID-19. Although turmeric inhibits cytochrome P450 enzymes, these effects seem to be clinically negligible. Caution when taken with drugs that are substrates of p-glycoprotein in order to avoid drug overdose. Although turmeric has hypoglycemic effects and might cause side effects such as fainting when combined with antidiabetic medications, this combination has shown to be safe in clinical trials.
Nigella sativa(black seed) – Anti-inflammatory and respiratory support
Nigella sativain COVID-19
Nigella sativain diabetes
Several clinical trials have been conducted to evaluate
Nigella sativain heart disease
In a meta-analysis including 11 randomized clinical trials with 860 hypertensive or normotensive individuals,
One of the main active constituents in
Nigella sativasafety summary
7. Interactions summary
The combination of several dietary ingredients might be desirable when their main mechanisms of action and clinical effects differ. For example, combination of an anti-inflammatory, antiviral, immunostimulant, and bronchodilator herbs might be recommended. Safety combination of black seed and turmeric has been demonstrated in a clinical study.
|Echinacea||None||None||Scarce: positive effect in 1 preclinical study||Induces CYP3A, inhibits CYP1A2, and CYP2C9||[27, 28, 29, 36, 38]|
|Licorice||Positive effects in vitro and 2 ongoing clinical trials||Negative effects in several clinical trials showing hypertension and hyperkalemia||Scarce: positive effects in 1 clinical, 1 preclinical, and 1 in vitro study||Safe dose <100 mg glycyrrhizin.|
Inhibits CYP1A2, 2B6, 2C8, 2C9, and 2C19. Only
|[45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 63, 64, 65, 66]|
|Turmeric||Positive effects in vitro and 1 completed clinical trial||Positive effects in several clinical trials||Positive effects in several clinical trials||Safe dose ≤250 mg. Inhibits p-glycoprotein and not clinically significant inhibition of P450 enzymes||[68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 88]|
|Black seed||Positive effects in vitro||Positive effects in several clinical trials||Positive effects in several clinical trials||Inhibits CYP2C9||[94, 96, 97, 98, 99, 100, 101, 102, 103, 104, 111, 112, 113, 114]|
All the four dietary ingredients discussed herein are safe for use short-term as in a setting of treating a disease. However, some might not be safe when taken long-term. For example, no safety data was found for echinacea in heart disease and diabetes. Long-term use of low dose or short-term use of high dose licorice can cause reversible hypertension. Hepatotoxicity might occur with long-term use of turmeric >250 mg/day. Lastly, all of these four dietary ingredients are metabolized by cytochrome P450 enzymes to some extent. Mostly they inhibit CYP2C9, 1A2 and 2B6. Caution with echinacea because it induces CYP3A4 and turmeric because it inhibits it.
Conflict of interest
The author declares no conflict of interest.