The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants and Herbal Products

*Cigdem Kahraman, Zekiye Ceren Arituluk and Iffet Irem Tatli Cankaya*

## **Abstract**

Approximately 70% of the world's population has been using medicinal herbs as a complementary or alternative medicine that has grown tremendously in both developed and developing countries over the past 20 years (World Health Organization Drugs Strategy 2002–2005). This increase in consumer demand for medicinal plants continues, although scientific data are rare to create safety and efficacy profiles. Its popularity is also related to easy availability, cost-effectiveness leading to better purchasing power, and various factors that perceive that they are generally safe. Herbs are often administered simultaneously with therapeutic drugs for the treatment of major ailments, and herb-drug interactions (HDIs) increase their potential. The main routes proposed for HDIs include cytochrome P450 (CYP450)-mediated inhibition or induction and transport and flow proteins. In our review, we highlighted herbal medicines used for the treatment of various diseases with pharmacokinetic, pharmacodynamic analysis and case reports together with their adverse effects and herb-drug interactions. Therefore, this review can be used as a quick reference database for physicians and healthcare professionals involved in therapy, aiming to maximize clinical outcomes by reducing the negative and toxic effects of plants along with avoiding herb-drug interactions.

**Keywords:** herbs/plants, herbal products, natural products, drugs, interactions, toxicity

## **1. Introduction**

Herbal products are considered the best choice as complementary medicine in western countries, especially in the United States and Europe. Annual sales of dietary herbal supplements in the United States increase 6.8% year over year. In addition, China and India are the top export countries, while Hong Kong, Japan, the United States, and Germany are the leading importers. The Confederation of Indian Industry (CII) presented that the market size of the Ayurvedic industry in the country is \$ 4.4 billion, and the total market size of the Indian health industry is \$ 11.8 billion. There has been an increase in demand for "complementary" medicines, including those of plant origin. In addition, there is a significant increase in the self-administration of herbal medicines among the public. In the context of the

growing demand and use of herbal medicines for patients and the public, and the subsequent interests of the regulatory authorities, comprehensive research on the safety and effectiveness of herbal products, including the possibility of interactions when simultaneous application is required, should be encouraged. This is because all herbal medicines and dietary supplements are a complex mixture containing multiple active phyto-components that increase the possibility of herb-drug interaction (HDI). Most people who consume herbal products and supplements do not show this to their pharmacist or doctor, thereby increasing the likelihood of HDI being identified and resolved over time. However, data from recent studies show that there is potential for serious interaction between some commonly used herbs/herbal products and commonly used standard medications [1].

In our review, we highlighted herbal medicines used for the treatment of various diseases with their adverse effects and herb-drug interactions, and stated recommendations for proper use of plants that might prevent possible risks for future incidents.

## **2. Toxicological risks of plants and herbal products**

General risks associated with herbs and/or herbal products include:


## **2.1 Nephrotoxicity**

The drug or toxin that causes kidney damage when exposed to a certain level cannot pass the excess urine, and the waste product is what is called nephrotoxicity. In this case, there is an increase in blood electrolytes, such as potassium and magnesium. This situation begins temporarily but can be serious if it is not detected before. Blood urea nitrogen (BUN) test and creatinine levels in the blood are two simple tests called as kidney function tests used to detect the nephrotoxicity. For healthy individuals, the normal levels of BUN and creatinine are between 10–25 mg/dl and 0.7–1.4 mg/dl, respectively. The following factors may increase these values:


**247**

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

h.Radiocontrast dye injected intravenously to improve visibility.

d.The aftermath of diseases such as diabetic neuropathy, congestive heart failure,

i. Drug toxicity with some chemotherapeutics (carboplatin, carmustine, cisplatin, methotrexate, and mitomycin) and biological therapeutic agents (interleukin-2 and interferon-alpha), antibiotics (amphotericin B, gentamicin, and vancomycin), NSAIDs (ibuprofen), diuretics (furosemide), and ACE inhibi-

The cause of nephrotoxicity after taking herbal medicine may be the addition of toxins during careless preparation, addition of adulterants, heavy metals, and some pharmaceutical products intentionally reducing costs or increasing effectiveness [3]. About 50 plants were related to kidney damage case reports published in PubMed in the last 50+ years (from 1966 to May 2016). Herbs include *Aristolochia fangchi* Y.C.Wu ex L.D.Chow & S.M.Hwang, *Artemisia herba-alba* Asso, *Callilepis laureola* DC., *Cupressus funebris* Endl., *Ephedra sinica* Stapf, *Hypericum perforatum* L., *Taxus celebica* (Warb.) H.L.Li, *Tribulus terrestris* L., and *Tripterygium wilfordii* Hook.f. *Aristolochia* species containing aristolochic acid, *Aristolochia fangchi*, had the

Hepatotoxicity ("Hepar*"* means liver and "Toxicon*"* means poison in ancient Greek) implies liver damage caused by medication, chemical, herbal, or dietary supplements. Stomach pain, vomiting, nausea, chance in urine and stool color, rash, jaundice, frequent tiredness, weakness, fatigue, and fever are the main symptoms of the damage. Some liver function tests performed on blood samples allow detecting hepatotoxicity in the laboratory. These tests include alanine transaminase test (normal range 7–55 U/l), alkaline phosphatase test (normal range 45–115 U/l), albumin test (normal range 3.5–5.0 g/dl), aspartate transaminase test (normal range 8–48 U/l), and bilirubin test (normal range 0.1–1.2 mg/dl). Increased ALT, ALP, AST, and bilirubin and decreased albumin levels demonstrate hepatotoxicity. The

The causes of liver damage are both hepatocellular and extracellular mechanisms

such as hepatocyte disruption, transport protein disruption, T-cell activation, hepatocyte apoptosis, disruption of mitochondria, injury of bile duct, drug toxicity,

*Drug toxicity mechanisms:* drugs are the main cause of hepatotoxicity. About 900 drugs, toxins, and herbs have been reported for hepatotoxicity. There are two types of drug reactions: the first is the reaction that directly affects the liver, called internal drug reactions; and the other is the reaction that mediates the immune response, called idiosyncratic drug reactions. In the first category, the drug itself or its metabolite produces a dose-dependent injury, such as paracetamol and carbon

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

e.Gastrointestinal bleeding.

f. Prolonged hypotension.

g.Protein-rich diets.

**2.2 Hepatotoxicity**

and drug interaction [3].

and enlarged prostate gland in man.

tors (captopril, benazepril, and enalapril).

j. Nephrotoxicity after taking herbal medicine.

highest number of publications (not actual cases) [4].

levels of ALP also increase during pregnancy [3].

c.Nephritis or urinary tract infection.

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*


*Medical Toxicology*

future incidents.

acids [2].

**2.1 Nephrotoxicity**

a.Dehydration.

irregular heart rhythms.

c.Nephritis or urinary tract infection.

growing demand and use of herbal medicines for patients and the public, and the subsequent interests of the regulatory authorities, comprehensive research on the safety and effectiveness of herbal products, including the possibility of interactions when simultaneous application is required, should be encouraged. This is because all herbal medicines and dietary supplements are a complex mixture containing multiple active phyto-components that increase the possibility of herb-drug interaction (HDI). Most people who consume herbal products and supplements do not show this to their pharmacist or doctor, thereby increasing the likelihood of HDI being identified and resolved over time. However, data from recent studies show that there is potential for serious interaction between some commonly used

herbs/herbal products and commonly used standard medications [1].

General risks associated with herbs and/or herbal products include:

resembling plants mistaken for herbs collected in the wild.

• Misidentification without assigning with Latin names. Possible causes of misidentification include contamination of cultivated plants with weeds, and

• Contamination with harmful substances such as heavy metals, polycyclic aromatic hydrocarbons, dioxins, as well as natural toxins or microorganisms.

• Interaction with other drugs, such as antagonism or synergism, and medical

• Intrinsic toxicity caused by the presence of natural toxins, such as aristolochic

The drug or toxin that causes kidney damage when exposed to a certain level cannot pass the excess urine, and the waste product is what is called nephrotoxicity. In this case, there is an increase in blood electrolytes, such as potassium and magnesium. This situation begins temporarily but can be serious if it is not detected before. Blood urea nitrogen (BUN) test and creatinine levels in the blood are two simple tests called as kidney function tests used to detect the nephrotoxicity. For healthy individuals, the normal levels of BUN and creatinine are between 10–25 mg/dl and 0.7–1.4 mg/dl, respectively. The following factors may increase these values:

b.Obstruction of blood flow to or from kidney caused by a tumor, stone, or

**2. Toxicological risks of plants and herbal products**

tests that potentially lead to misdiagnosis.

• Adulteration with other medicinal drugs.

In our review, we highlighted herbal medicines used for the treatment of various diseases with their adverse effects and herb-drug interactions, and stated recommendations for proper use of plants that might prevent possible risks for

**246**


The cause of nephrotoxicity after taking herbal medicine may be the addition of toxins during careless preparation, addition of adulterants, heavy metals, and some pharmaceutical products intentionally reducing costs or increasing effectiveness [3].

About 50 plants were related to kidney damage case reports published in PubMed in the last 50+ years (from 1966 to May 2016). Herbs include *Aristolochia fangchi* Y.C.Wu ex L.D.Chow & S.M.Hwang, *Artemisia herba-alba* Asso, *Callilepis laureola* DC., *Cupressus funebris* Endl., *Ephedra sinica* Stapf, *Hypericum perforatum* L., *Taxus celebica* (Warb.) H.L.Li, *Tribulus terrestris* L., and *Tripterygium wilfordii* Hook.f. *Aristolochia* species containing aristolochic acid, *Aristolochia fangchi*, had the highest number of publications (not actual cases) [4].

#### **2.2 Hepatotoxicity**

Hepatotoxicity ("Hepar*"* means liver and "Toxicon*"* means poison in ancient Greek) implies liver damage caused by medication, chemical, herbal, or dietary supplements. Stomach pain, vomiting, nausea, chance in urine and stool color, rash, jaundice, frequent tiredness, weakness, fatigue, and fever are the main symptoms of the damage. Some liver function tests performed on blood samples allow detecting hepatotoxicity in the laboratory. These tests include alanine transaminase test (normal range 7–55 U/l), alkaline phosphatase test (normal range 45–115 U/l), albumin test (normal range 3.5–5.0 g/dl), aspartate transaminase test (normal range 8–48 U/l), and bilirubin test (normal range 0.1–1.2 mg/dl). Increased ALT, ALP, AST, and bilirubin and decreased albumin levels demonstrate hepatotoxicity. The levels of ALP also increase during pregnancy [3].

The causes of liver damage are both hepatocellular and extracellular mechanisms such as hepatocyte disruption, transport protein disruption, T-cell activation, hepatocyte apoptosis, disruption of mitochondria, injury of bile duct, drug toxicity, and drug interaction [3].

*Drug toxicity mechanisms:* drugs are the main cause of hepatotoxicity. About 900 drugs, toxins, and herbs have been reported for hepatotoxicity. There are two types of drug reactions: the first is the reaction that directly affects the liver, called internal drug reactions; and the other is the reaction that mediates the immune response, called idiosyncratic drug reactions. In the first category, the drug itself or its metabolite produces a dose-dependent injury, such as paracetamol and carbon

tetrachloride. In the second category, hypersensitivity reactions, for example, phenytoin reaction, cause an immunoallergic or metabolic idiosyncratic reaction due to fever, rash, eosinophilia and indirect drug reaction for a short time. The second reaction type response rate is variable, for example, halothane [3].

*Drug interaction mechanisms*: when some drugs are taken at the same time, they react together and cause liver damage. For example, the combination of tylenol with INH, histamine, laniazide, and nydrazide can be hepatotoxic [3].

When hepatotoxicity caused by herbal drug intake is discussed, case rates are often reported. The severity of toxicity varies greatly between mild hepatitis and acute liver failure. The scoring system for allopathic drugs can be evaluated, but not suitable for herbal medicines and needs validation. Many Ayurvedic and Chinese herbal medicines are reported to cause hepatotoxicity. The main hepatotoxic herbs are *Cimicifuga racemosa* (L.) Nutt., *Larrea tridentata (*Sessé & Moc. ex DC.) Coville, *Scutellaria baicalensis* Georgi, *Scutellaria lateriflora* L., *Teucrium chamaedrys* L., etc. [3].

## **2.3 Cardiotoxicity**

Cardiotoxicity is a term used for damage to the heart or change heart functions. It is a condition where there is a change in the electrophysiological function of the heart or damage to the heart muscle, weakening the heart and causing poor blood circulation. This can be detected by symptoms such as dry, unproductive cough; inflammation in the ankles, hands, feet, and neck vessels; irregular heartbeat; tachycardia; cardiomegaly; weakness; dizziness; etc. [3].

Herbal drugs that have a direct effect on the heart include medicine prepared from plants such as *Aconitum napellus* L*.*, *Atropa belladonna* L., *Catharanthus roseus* (L.) G.Don, *Digitalis purpurea* L*.*, *Ephedra distachya* L., *Glycyrrhiza glabra* L., *Mandragora officinarum* L., etc. [3].

## *2.3.1 Potential precautions of plants on hypertension*

Herbal products are widely used in the general population and many are encouraged for the natural treatment of hypertension. Patients with hypertension often prefer to use these products in addition to or instead of pharmacological antihypertensive agents. Due to the frequent use of herbal products, both consumers and healthcare providers should be aware of the major issues surrounding these products and factors affecting both effectiveness and damages (**Table 1**) [5].


**249**

**Table 2.**

*\**

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

mon medicinal herbs that have potential neurotoxic effects [3].

*Panax ginseng* C.A.Mey. Insomnia, vaginal bleeding, mastalgia, mania

*2.4.1 Psychiatric and neurological adverse effects*

The physical brain damage occurred by exposure to neurotoxin is stated as neurotoxicity. Neurotoxin is a substance that causes changes in the nervous system activity by disrupting or killing neurons. Neurotoxicity symptoms are generally emotional disorders, visual impairment, extremity failing, sexual dysfunction, headache, and behavioral alteration. *Atropa belladonna*, *Brugmansia* species, *Catharanthus roseus*, *Cannabis sativa* L., *Conium maculatum* L., *Coscinium fenestratum* (Goetgh.) Colebr*.*, *Datura stramonium* L., *Hyoscyamus niger* L., and *Papaver somniferum* L. are the com-

Psychiatric and neurological patients often try herbal medicines assuming they are safe. Numerous case reports include various adverse events such as cerebral arteritis, cerebral edema, delirium, coma, confusion, encephalopathy, hallucinations, intracerebral hemorrhage and other cerebrovascular accidents, movement disorders, mood disorders, muscle weakness, paresthesia, and seizures. Some deaths have been recorded. Misuse is caused by toxicity of herbal ingredients, contamination and adulteration, and herb-drug interactions [6] (**Table 2**).

**Herbs Adverse effects Potential drug interactions**

Ataxia, blurred vision, disorientation,

Nausea, drowsiness, ventricular

hallucination, liver failure

GI symptoms and cramps, confusion,

GI symptoms, restlessness, allergies,

Anxiety, confusion, insomnia,

Dryness of mouth, nausea, GI symptoms, leukopenia

*Although we know the unconscious use of plants or their products, some of the plants given in the table are potent plants that are undesirable to be used in phytotherapy, but they are generally used in Traditional Chinese Medicine.*

*Eucalyptus* sp. Cyanosis, delirium, GI symptoms Not known

other cholinergic signs

tachycardia

hepatitis

psychosis

dizziness, bleeding

*Ginkgo biloba* L. GI symptoms, allergies, headache,

*Aconitum* sp. (Aconite)\* Acidosis, bradycardia, diarrhea,

*Herbal remedies implicated in causing neurological adverse effects [6].*

hypokalemia

Headache, GI symptoms, hangover Other CNS depressants

Mineral corticoid effects Antihypertensives,

Phenelzine, hypoglycemic drugs

Other anti-cholinergic agents

corticosteroids, digoxin

Other CNS depressants

Other CNS depressants

Other CNS-stimulants, beta-blockers, MAO-inhibitors, phenothiazines, theophylline

hepatic enzyme inducer

Antiarrhythmics, antihypertensives

Anticoagulants

Not known

GI symptoms, allergies, fatigue, anxiety Serotonin reuptake inhibitors,

system

Inhibitors of cytochrome P-450

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

**2.4 Neurotoxicity**

*Valeriana officinalis* L.

*Datura stramonium* (Jimson weed)\*

*Glycyrrhiza glabra* (Licorice)

*Passiflora incarnata* L. (Passionflower)

*Mentha pulegium* L. (Pennyroyale)

*Ephedra sinica* (Ma Huang)\*

*Tripterygium wilfordii (*Thunder God Vine)\*

*Hypericum perforatum* (St.

John's wort)

(Kava)\*

*Piper methysticum* G.Forst.

(Valerian)

**Table 1.**

*Herbal/natural products in hypertension for their benefits and disadvantages.*

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

### **2.4 Neurotoxicity**

*Medical Toxicology*

**2.3 Cardiotoxicity**

**Herbal/natural products for evidence of benefit**

*Allium sativum* L. (Garlic)

tetrachloride. In the second category, hypersensitivity reactions, for example, phenytoin reaction, cause an immunoallergic or metabolic idiosyncratic reaction due to fever, rash, eosinophilia and indirect drug reaction for a short time. The second

*Drug interaction mechanisms*: when some drugs are taken at the same time, they react together and cause liver damage. For example, the combination of tylenol with

When hepatotoxicity caused by herbal drug intake is discussed, case rates are often reported. The severity of toxicity varies greatly between mild hepatitis and acute liver failure. The scoring system for allopathic drugs can be evaluated, but not suitable for herbal medicines and needs validation. Many Ayurvedic and Chinese herbal medicines are reported to cause hepatotoxicity. The main hepatotoxic herbs are *Cimicifuga racemosa* (L.) Nutt., *Larrea tridentata (*Sessé & Moc. ex DC.) Coville, *Scutellaria baicalensis* Georgi, *Scutellaria lateriflora* L., *Teucrium chamaedrys* L., etc. [3].

Cardiotoxicity is a term used for damage to the heart or change heart functions. It is a condition where there is a change in the electrophysiological function of the heart or damage to the heart muscle, weakening the heart and causing poor blood circulation. This can be detected by symptoms such as dry, unproductive cough; inflammation in the ankles, hands, feet, and neck vessels; irregular heartbeat;

Herbal drugs that have a direct effect on the heart include medicine prepared from plants such as *Aconitum napellus* L*.*, *Atropa belladonna* L., *Catharanthus roseus* (L.) G.Don, *Digitalis purpurea* L*.*, *Ephedra distachya* L., *Glycyrrhiza glabra* L.,

Herbal products are widely used in the general population and many are encouraged for the natural treatment of hypertension. Patients with hypertension often prefer to use these products in addition to or instead of pharmacological antihypertensive agents. Due to the frequent use of herbal products, both consumers and healthcare providers should be aware of the major issues surrounding these prod-

**Causes**

seizures

healthy people

palpitations

palpitations, tachycardia, stroke,

Hypertension, tachycardia,

subsequent hypertension

ucts and factors affecting both effectiveness and damages (**Table 1**) [5].

Coenzyme Q10 *Ephedra* spec. (Ephedra) Cardiac effects, hypertension,

Fish oil *Citrus × aurantium* L. (Bitter orange) Blood pressure increases occur in

Vitamin C *Glycyhrriza glabra* (Licorice) Mineralocorticoid excess syndrome,

*Eleutherococcus senticosus* (Rupr. & Maxim.) Maxim. (Siberian Ginseng)

*Herbal/natural products in hypertension for their benefits and disadvantages.*

**Herbs/herbal products for evidence of harm**

reaction type response rate is variable, for example, halothane [3].

INH, histamine, laniazide, and nydrazide can be hepatotoxic [3].

tachycardia; cardiomegaly; weakness; dizziness; etc. [3].

*2.3.1 Potential precautions of plants on hypertension*

*Mandragora officinarum* L., etc. [3].

**248**

**Table 1.**

The physical brain damage occurred by exposure to neurotoxin is stated as neurotoxicity. Neurotoxin is a substance that causes changes in the nervous system activity by disrupting or killing neurons. Neurotoxicity symptoms are generally emotional disorders, visual impairment, extremity failing, sexual dysfunction, headache, and behavioral alteration. *Atropa belladonna*, *Brugmansia* species, *Catharanthus roseus*, *Cannabis sativa* L., *Conium maculatum* L., *Coscinium fenestratum* (Goetgh.) Colebr*.*, *Datura stramonium* L., *Hyoscyamus niger* L., and *Papaver somniferum* L. are the common medicinal herbs that have potential neurotoxic effects [3].

### *2.4.1 Psychiatric and neurological adverse effects*

Psychiatric and neurological patients often try herbal medicines assuming they are safe. Numerous case reports include various adverse events such as cerebral arteritis, cerebral edema, delirium, coma, confusion, encephalopathy, hallucinations, intracerebral hemorrhage and other cerebrovascular accidents, movement disorders, mood disorders, muscle weakness, paresthesia, and seizures. Some deaths have been recorded. Misuse is caused by toxicity of herbal ingredients, contamination and adulteration, and herb-drug interactions [6] (**Table 2**).


**Table 2.**

*Herbal remedies implicated in causing neurological adverse effects [6].*

#### **2.5 Skin toxicity**

Cutaneous toxicity is a term used for a pronounced negative effect such as skin irritation, inflammation, or rashes of the epidermal growth factor receptor caused by exposure to a plant, chemical, or environmental factor. Skin consisting of a layer of dead cells and several layers of living cells is the largest organ and a defensive barrier of the body. When irritant influences into the skin, the living cells react due to cause inflammation or dermatitis. Inflammation consists of four parts including redness, pain, heat, and swelling. Skin toxicity can be detected easily as the reaction is observed immediately. The most common sources of skin toxicity are food and cosmetics, and others are medicated lotions, balms, creams, inhalers, and essential oils. Various herbal ingredients are available in all the cosmetics and medicinal products mentioned above. Types of skin sensitization reactions include:

*Primary irritant dermatitis*: it is a direct irritation of the skin, such as redness, itching, pain, blusters, peeling, or open wounds. Primary irritant dermatitis may be caused by plants such as, *Asclepias syriaca* L., *Cannabis sativa*, *Dieffenbachia amoena* Bull*.*, *Digitalis purpurea*, *Ficus carica* L., *Hevea brasiliensis* (Willd. ex A.Juss.) Müll. Arg., *Narcissus pseudonarcissus* L*.*, *Primula veris* L*.*, *Ranunculus acris* L., *Ricinus communis* L., *Tulipa gesneriana* L., etc. Common foods such as *Agaricus bisporus* L*.*, *Apium graveolens* L*., Brassica rapa* L., *Cucumis sativus* L., *Daucus carota* L., *Pastinaca sativa* L*.*, *Petroselinum crispum* (Mill.) Fuss, and *Solanum lycopersicum* L. can also cause primary irritant dermatitis.

*Allergic contact dermatitis*: it is a real allergic response and varies from person to person. *Toxicodendron diversilobum* (Torr. & A.Gray) Greena and *Toxicodendron rydbergii* (Small ex Rydb.) Greene, *Allium cepa* L., *Allium sativum, Anacardium occidentale* L., *Apium graveolens, Cedrus deodara* (Roxb. ex D.Don) G.Don, *Dendranthema grandiflorum* (Ramat.) Kitam*.*, *Hedera helix* L., *Marchantiophyta* species*, Narcissus pseudonarcissus*, *Primula vulgaris* Huds*.*, *Pinus sabiniana* Douglas, *Toxicodendron vernix* (L.) Kuntze, and *Tulipa gesneriana* are the most common plants that produce allergic contact dermatitis.

*Photosensitization dermatitis*: it is a cutaneous toxic response caused by exposure to sunlight when a photosensitizer (sunlight sensitive compound) is present in the body and can be detected by sunburn-like reactions in pigment-free areas. Plants such as *Agave lechuguilla* Torr., *Bassia scoparia* (L.) A.J.Scott*, Hypericum* species (St John's wort), *Lantana camara* L*.*, *Tetradymia* species, and *Tribulus terrestris* cause photosensitive dermatitis [3].

There is another type of phototoxic photosensitization caused by contact with some plants. Such a reaction occurs when a photoactive chemical produced by plants touches the skin, and is absorbed and activated by sunlight. Intensity varies depending on time and exposure amount. *Anethum graveolens* L., *Apium graveolens* L.*, Brassica oleracea* L., *Citrus aurantiifolia* (Christm.) Swingle, *Daucus carota*, *Ficus carica*, *Hypericum perforatum* (St. John's wort), *Petroselinum crispum*, and *Ranunculus acris* are reported to produce contact photosensitization [3].

### **3. Contamination of herbal medicines by tropane alkaloids**

Tropane alkaloids that have been known as toxic and hallucinogenic are mainly seen in Solanaceae plants (*Atropa belladonna*, *Hyoscyamus niger*, *Datura stramonium*, etc.). All over the world, anticholinergic poisoning is observed due to the contamination of herbal teas and plants with tropane alkaloids. Tropane alkaloid poisoning can occur after consumption of any medicinal plant from Solanaceae family as contaminants. Globally, almost all reports from 1978 to 2014 include one

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*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

of the herbs prescribed in herbal teas. Contamination is most likely to occur during harvesting or processing. For herbs, on-site inspection is required to exclude crosscontamination at the retail level and accidental mixing. The diagnosis is confirmed by screening for the presence of Solanaceae species and tropane alkaloids. Since, if these relatively heat-resistant alkaloids contaminate the herbal teas and other herbs in large quantities, significant health hazards may occur, the significance of good agricultural and collection practices (GACPs) for medicinal plants is accentuated by WHO repeatedly. The DNA barcode is also increasingly used to exclude the presence of pollutant (especially toxic species) and product substitution. All suspect cases should be reported to health authorities so that investigations throughout the supply chain and early intervention measures to protect the public can be taken [7].

**4. Herb-drug interactions with the plants including furanocoumarins**

drug interactions were first discovered by chance in 1989 where 5-fold higher felodipine plasma concentrations were observed. Consumption of grapefruit juice has increased the oral bioavailability of various drugs, including calcium channel blockers (e.g., felodipine, nifedipine), HMG-CoA reductase inhibitors (simvastatin, lovastatin), benzodiazepines (midazolam, triazolam), antihistamines (terfenadines), and immunosuppressants (cyclosporine). In addition, phototoxicity developing with furanocoumarins occurs as a result of exposure to sunlight, following contact with the plant. Phototoxicity results in acute dermatitis, sometimes blisters, and vesicles. In many cases, prolonged hyperpigmentation is observed. Photochemotherapy for a

long time with furanocoumarins can also cause cancer (skin and liver) [8].

Pyrrolizidine alkaloids (PAs) are common components of hundreds of plant species of unrelated botanical families scattered across many geographical regions of the world. In more than 6000 plants belonging to three large plant families, Asteraceae, Boraginaceae, and Fabaceae, above 660 PAs and PA *N-oxides* have been identified and about half of them are toxic. More than 10,000 cases of PAs poisoning have been documented worldwide, most of which resulted from exposure to food contaminated with PAs. Acute toxicity from PA is mainly seen in the liver, including hemorrhagic necrosis, hepatic megalocytosis, venous occlusion, liver cirrhosis, and hepatic carcinomas, and chronic exposure to PAs, from herbs/dietary products containing PAs, can lead to kidneys, pancreas, gastrointestinal tract, bone marrow, and brain. It is a worldwide public health problem due to the high risk of human exposure to genotoxic and tumorigenic PAs, and the International Program on Chemical Safety has concluded that PAs are a threat to human health and safety.

Anthraquinone derivatives with a laxative effect appear in a number of plants:

*Sennae folium*, rhei rhizoma, frangulae cortex, and aloe. They have a laxative effect by directly stimulating the colonic smooth muscles. The adverse effects of laxative anthraquinone drugs are more likely to be caused by excessive loss of

**5. Toxicity of pyrrolizidine alkaloids**

Regulations have been constituted to restrict its use [8].

**6. Adverse effects of anthraquinone derivatives**

Naturally occurring furanocoumarins are abundant in citrus fruits, vegetables, and medicinal herbs from the Apiaceae, Fabaceae, and Rutaceae families. Grapefruit-

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

of the herbs prescribed in herbal teas. Contamination is most likely to occur during harvesting or processing. For herbs, on-site inspection is required to exclude crosscontamination at the retail level and accidental mixing. The diagnosis is confirmed by screening for the presence of Solanaceae species and tropane alkaloids. Since, if these relatively heat-resistant alkaloids contaminate the herbal teas and other herbs in large quantities, significant health hazards may occur, the significance of good agricultural and collection practices (GACPs) for medicinal plants is accentuated by WHO repeatedly. The DNA barcode is also increasingly used to exclude the presence of pollutant (especially toxic species) and product substitution. All suspect cases should be reported to health authorities so that investigations throughout the supply chain and early intervention measures to protect the public can be taken [7].

## **4. Herb-drug interactions with the plants including furanocoumarins**

Naturally occurring furanocoumarins are abundant in citrus fruits, vegetables, and medicinal herbs from the Apiaceae, Fabaceae, and Rutaceae families. Grapefruitdrug interactions were first discovered by chance in 1989 where 5-fold higher felodipine plasma concentrations were observed. Consumption of grapefruit juice has increased the oral bioavailability of various drugs, including calcium channel blockers (e.g., felodipine, nifedipine), HMG-CoA reductase inhibitors (simvastatin, lovastatin), benzodiazepines (midazolam, triazolam), antihistamines (terfenadines), and immunosuppressants (cyclosporine). In addition, phototoxicity developing with furanocoumarins occurs as a result of exposure to sunlight, following contact with the plant. Phototoxicity results in acute dermatitis, sometimes blisters, and vesicles. In many cases, prolonged hyperpigmentation is observed. Photochemotherapy for a long time with furanocoumarins can also cause cancer (skin and liver) [8].

## **5. Toxicity of pyrrolizidine alkaloids**

Pyrrolizidine alkaloids (PAs) are common components of hundreds of plant species of unrelated botanical families scattered across many geographical regions of the world. In more than 6000 plants belonging to three large plant families, Asteraceae, Boraginaceae, and Fabaceae, above 660 PAs and PA *N-oxides* have been identified and about half of them are toxic. More than 10,000 cases of PAs poisoning have been documented worldwide, most of which resulted from exposure to food contaminated with PAs. Acute toxicity from PA is mainly seen in the liver, including hemorrhagic necrosis, hepatic megalocytosis, venous occlusion, liver cirrhosis, and hepatic carcinomas, and chronic exposure to PAs, from herbs/dietary products containing PAs, can lead to kidneys, pancreas, gastrointestinal tract, bone marrow, and brain. It is a worldwide public health problem due to the high risk of human exposure to genotoxic and tumorigenic PAs, and the International Program on Chemical Safety has concluded that PAs are a threat to human health and safety. Regulations have been constituted to restrict its use [8].

#### **6. Adverse effects of anthraquinone derivatives**

Anthraquinone derivatives with a laxative effect appear in a number of plants: *Sennae folium*, rhei rhizoma, frangulae cortex, and aloe. They have a laxative effect by directly stimulating the colonic smooth muscles. The adverse effects of laxative anthraquinone drugs are more likely to be caused by excessive loss of

*Medical Toxicology*

**2.5 Skin toxicity**

cause primary irritant dermatitis.

photosensitive dermatitis [3].

plants that produce allergic contact dermatitis.

Cutaneous toxicity is a term used for a pronounced negative effect such as skin irritation, inflammation, or rashes of the epidermal growth factor receptor caused by exposure to a plant, chemical, or environmental factor. Skin consisting of a layer of dead cells and several layers of living cells is the largest organ and a defensive barrier of the body. When irritant influences into the skin, the living cells react due to cause inflammation or dermatitis. Inflammation consists of four parts including redness, pain, heat, and swelling. Skin toxicity can be detected easily as the reaction is observed immediately. The most common sources of skin toxicity are food and cosmetics, and others are medicated lotions, balms, creams, inhalers, and essential oils. Various herbal ingredients are available in all the cosmetics and medicinal products mentioned above. Types of skin sensitization reactions include:

*Primary irritant dermatitis*: it is a direct irritation of the skin, such as redness, itching, pain, blusters, peeling, or open wounds. Primary irritant dermatitis may be caused by plants such as, *Asclepias syriaca* L., *Cannabis sativa*, *Dieffenbachia amoena* Bull*.*, *Digitalis purpurea*, *Ficus carica* L., *Hevea brasiliensis* (Willd. ex A.Juss.) Müll. Arg., *Narcissus pseudonarcissus* L*.*, *Primula veris* L*.*, *Ranunculus acris* L., *Ricinus communis* L., *Tulipa gesneriana* L., etc. Common foods such as *Agaricus bisporus* L*.*, *Apium graveolens* L*., Brassica rapa* L., *Cucumis sativus* L., *Daucus carota* L., *Pastinaca sativa* L*.*, *Petroselinum crispum* (Mill.) Fuss, and *Solanum lycopersicum* L. can also

*Allergic contact dermatitis*: it is a real allergic response and varies from person to person. *Toxicodendron diversilobum* (Torr. & A.Gray) Greena and *Toxicodendron rydbergii* (Small ex Rydb.) Greene, *Allium cepa* L., *Allium sativum, Anacardium occidentale* L., *Apium graveolens, Cedrus deodara* (Roxb. ex D.Don) G.Don, *Dendranthema grandiflorum* (Ramat.) Kitam*.*, *Hedera helix* L., *Marchantiophyta* species*, Narcissus pseudonarcissus*, *Primula vulgaris* Huds*.*, *Pinus sabiniana* Douglas, *Toxicodendron vernix* (L.) Kuntze, and *Tulipa gesneriana* are the most common

*Photosensitization dermatitis*: it is a cutaneous toxic response caused by exposure to sunlight when a photosensitizer (sunlight sensitive compound) is present in the body and can be detected by sunburn-like reactions in pigment-free areas. Plants such as *Agave lechuguilla* Torr., *Bassia scoparia* (L.) A.J.Scott*, Hypericum* species (St John's wort), *Lantana camara* L*.*, *Tetradymia* species, and *Tribulus terrestris* cause

There is another type of phototoxic photosensitization caused by contact with some plants. Such a reaction occurs when a photoactive chemical produced by plants touches the skin, and is absorbed and activated by sunlight. Intensity varies depending on time and exposure amount. *Anethum graveolens* L., *Apium graveolens* L.*, Brassica oleracea* L., *Citrus aurantiifolia* (Christm.) Swingle, *Daucus carota*, *Ficus carica*, *Hypericum perforatum* (St. John's wort), *Petroselinum crispum*, and *Ranunculus acris* are reported to produce contact photosensitization [3].

Tropane alkaloids that have been known as toxic and hallucinogenic are mainly seen in Solanaceae plants (*Atropa belladonna*, *Hyoscyamus niger*, *Datura stramonium*, etc.). All over the world, anticholinergic poisoning is observed due to the contamination of herbal teas and plants with tropane alkaloids. Tropane alkaloid poisoning can occur after consumption of any medicinal plant from Solanaceae family as contaminants. Globally, almost all reports from 1978 to 2014 include one

**3. Contamination of herbal medicines by tropane alkaloids**

**250**

fluids and electrolytes, especially potassium loss, associated with the use of high doses. Higher doses also drain a larger portion of the colon, and the resulting natural absence of defecation over the next day leads to reuse of anthraquinone. Prolonged use of laxatives due to laxative addiction should be avoided, as it may have a detrimental effect on the intestinal mucosa, leading to a condition known as Melanosis coli. This is usually seen after at least 9–12 months of regular stimulant laxative use. Undesirable effects such as abdominal spasms and pain, urine color change by metabolites, and hemorrhoid congestion are common. A report from China reported that patients with senna leaf tea addiction as laxatives suffer from symptoms of fidgetiness, sleeplessness, dilated pupils, and loss of appetite while consuming 5–9 g of senna daily. Rare cases of hepatic inflammation induced by anthraquinone derivatives have been reported and may be dose dependent. Hypokalemia, which occurs as the effect of long-term use of laxative drugs, strengthens the effect of cardiac glycosides and interacts with antiarrhythmic drugs. Using other drugs (diuretics, adrenocorticosteroids, and licorice) that cause hypokalemia can speed up electrolyte imbalance. Contraindications for anthracene laxatives are intestinal obstruction and chronic intestinal inflammation such as stomach or duodenal ulcer or ulcerative colitis [9].

## **7. Adulterations**

Many reports on the adulteration of herbal products with synthetic drugs have been systematically reviewed and published with case reports. The list of herbal products and adulterants produced in this way is quite impressive and caused serious side effects (**Table 3**). A case with the latest herbal product adulterated is related to a 56-year-old man from Indonesia. While visiting Australia, he was hospitalized in a mixed condition arising from hypoglycemia. He insisted that type II diabetes was controlled only by diet. However, despite dextrose infusions, glucose levels do not normalize. It was eventually discovered that he also received a TCM "Zhen Qi" from Malaysia. It was analyzed and shown to contain glibenclamide. Like that, in some cases, patients were severely damaged. Examples of serious side effects include agranulocytosis, Cushing's syndrome, coma, over-anticoagulation, gastrointestinal bleeding, arrhythmias, and various skin lesions. Due to the adulteration of herbal products with synthetic drugs, adequate and necessary procedures should be applied, and whole herbal products should be analyzed before marketing [10].


**253**

**Figure 1.**

*conventional drugs [13].*

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

It is possible to come across heavy metals such as cadmium, cobalt, copper, iron, manganese, nickel, lead, zinc, and mercury in concentrations that are not produced within the framework of certain rules, especially the traditional Chinese herbal preparations. This contamination is probably caused by contamination during drying and preservation. With severe complications that may occur, these types of products are unlikely to cause adverse health effects, even if they are not consumed

There are no molecules in nature that have no effect. Therefore, this diversity increases the variety of products while increasing the probability of interaction. If the effect of a drug is changed qualitatively or quantitatively by another substance (herbal medicine/product/ingredient), there is an interaction between these two drugs. It can be said as a rule that two drugs should be present at the same time in the body, especially in the place of interaction, for interaction to occur. But sometimes, if the drug causes a permanent effect on the body, interaction can occur even if such a drug is not found in the body. Interaction is sometimes deliberately created to increase the therapeutic effect of one drug with another drug or to reduce its side effects, which are useful interactions. In other cases, the interaction may occur undesirably as a result of unauthorized use of medicines or when the patient is starting treatment with a particular medication. Sometimes, unpredictable interactions due to new drugs may occur. Drug-related as well as disease-related factors (patient's age, gender, genetic characteristics, pathological condition), such as the posology and method of administration, pharmacokinetic, pharmacodynamic, and therapeutic properties of the drug may cause interactions between medicines and herbal medicines (**Figure 1**) [12]. It is observed that the use of herbal medicines/herbal products is more common in the geriatric group aged 65 and over, and the use in women in this adult population is higher than in men. Herbs/herbal products/drug interaction is higher in patients using drugs with narrow therapeutic index. Information on herbs-herbal products/ drug/component interactions is based on *in vitro* tests, *in vivo* animal experiments,

*The important risk factors that influence the occurrence of interactions between herbal products and* 

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

in large quantities for long periods of time [11].

**9. Herb-drug interactions (HDI)**

**8. Heavy metal contaminations**

#### **Table 3.** *Adulterants found in herbal products.*

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

## **8. Heavy metal contaminations**

*Medical Toxicology*

**7. Adulterations**

before marketing [10].

fluids and electrolytes, especially potassium loss, associated with the use of high doses. Higher doses also drain a larger portion of the colon, and the resulting natural absence of defecation over the next day leads to reuse of anthraquinone. Prolonged use of laxatives due to laxative addiction should be avoided, as it may have a detrimental effect on the intestinal mucosa, leading to a condition known as Melanosis coli. This is usually seen after at least 9–12 months of regular stimulant laxative use. Undesirable effects such as abdominal spasms and pain, urine color change by metabolites, and hemorrhoid congestion are common. A report from China reported that patients with senna leaf tea addiction as laxatives suffer from symptoms of fidgetiness, sleeplessness, dilated pupils, and loss of appetite while consuming 5–9 g of senna daily. Rare cases of hepatic inflammation induced by anthraquinone derivatives have been reported and may be dose dependent. Hypokalemia, which occurs as the effect of long-term use of laxative drugs, strengthens the effect of cardiac glycosides and interacts with antiarrhythmic drugs. Using other drugs (diuretics, adrenocorticosteroids, and licorice) that cause hypokalemia can speed up electrolyte imbalance. Contraindications for anthracene laxatives are intestinal obstruction and chronic intestinal inflammation such as

Many reports on the adulteration of herbal products with synthetic drugs have been systematically reviewed and published with case reports. The list of herbal products and adulterants produced in this way is quite impressive and caused serious side effects (**Table 3**). A case with the latest herbal product adulterated is related to a 56-year-old man from Indonesia. While visiting Australia, he was hospitalized in a mixed condition arising from hypoglycemia. He insisted that type II diabetes was controlled only by diet. However, despite dextrose infusions, glucose levels do not normalize. It was eventually discovered that he also received a TCM "Zhen Qi" from Malaysia. It was analyzed and shown to contain glibenclamide. Like that, in some cases, patients were severely damaged. Examples of serious side effects include agranulocytosis, Cushing's syndrome, coma, over-anticoagulation, gastrointestinal bleeding, arrhythmias, and various skin lesions. Due to the adulteration of herbal products with synthetic drugs, adequate and necessary procedures should be applied, and whole herbal products should be analyzed

**Acetaminophen Dexamethasone Glibenclamide** Aminopyrine Dexamethasone acetate Hydrochlorothiazide Betamethasone Diazepam Hydrocortisone Caffeine Diclofenac Indomethacin Chlordiazepoxide Ethoxybenzamide Mefenamic acid Chlorzoxazone Fluocinolone acetonide Methylsalicylate Clobetasol propionate Fluocortolone Phenacetin Corticosteroids Fluocortolone Phenylbutazone Phenytoin Prednisolone Sibutramin

stomach or duodenal ulcer or ulcerative colitis [9].

**252**

**Table 3.**

Sildenafil

*Adulterants found in herbal products.*

It is possible to come across heavy metals such as cadmium, cobalt, copper, iron, manganese, nickel, lead, zinc, and mercury in concentrations that are not produced within the framework of certain rules, especially the traditional Chinese herbal preparations. This contamination is probably caused by contamination during drying and preservation. With severe complications that may occur, these types of products are unlikely to cause adverse health effects, even if they are not consumed in large quantities for long periods of time [11].

## **9. Herb-drug interactions (HDI)**

There are no molecules in nature that have no effect. Therefore, this diversity increases the variety of products while increasing the probability of interaction. If the effect of a drug is changed qualitatively or quantitatively by another substance (herbal medicine/product/ingredient), there is an interaction between these two drugs. It can be said as a rule that two drugs should be present at the same time in the body, especially in the place of interaction, for interaction to occur. But sometimes, if the drug causes a permanent effect on the body, interaction can occur even if such a drug is not found in the body. Interaction is sometimes deliberately created to increase the therapeutic effect of one drug with another drug or to reduce its side effects, which are useful interactions. In other cases, the interaction may occur undesirably as a result of unauthorized use of medicines or when the patient is starting treatment with a particular medication. Sometimes, unpredictable interactions due to new drugs may occur. Drug-related as well as disease-related factors (patient's age, gender, genetic characteristics, pathological condition), such as the posology and method of administration, pharmacokinetic, pharmacodynamic, and therapeutic properties of the drug may cause interactions between medicines and herbal medicines (**Figure 1**) [12].

It is observed that the use of herbal medicines/herbal products is more common in the geriatric group aged 65 and over, and the use in women in this adult population is higher than in men. Herbs/herbal products/drug interaction is higher in patients using drugs with narrow therapeutic index. Information on herbs-herbal products/ drug/component interactions is based on *in vitro* tests, *in vivo* animal experiments,

#### **Figure 1.**

*The important risk factors that influence the occurrence of interactions between herbal products and conventional drugs [13].*

and case reports. Many mechanisms play a role in these interactions, and interactions are seen in two main types as pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic interactions result in changes in drug absorption, distribution, metabolism, and elimination. These interactions usually occur far away from the drug's effect and lead to a decrease or increase in effect as a result of the change in drug concentration in body fluids. In order to say that there is a pharmacokinetic interaction, the plasma level or half-life of the drug should be determined experimentally. Various interactions such as cytochrome P450, UDP-glucuronyl-transferase (UGTs), and carrier proteins such as P-glycoprotein (P-gp) are thought to play a role in these interactions. Pharmacokinetic interactions are the most common interactions as a cause of undesirable side effects. If the herb or natural products or its secondary metabolites inhibit an enzyme involved in drug metabolism, it may increase the potential for toxic effects, as it will reduce the metabolism of drugs that metabolize the enzyme and turn into an inactive metabolite as a result of metabolism. If the herbal drug induces an enzyme, a decrease in drug effect may be observed, since the metabolism of the drugs that are metabolized by this enzyme and converted into inactive metabolite as a result of metabolism will increase. Likewise, if the drug turns into an active metabolite as a result of metabolism, if the herbal drug induces the enzyme responsible for the metabolism of the drug, an increase in drug effect or toxic effect may be observed as a result of increased effective metabolite concentration [12].

Pharmacodynamic interactions occur when one drug changes the effect of another, that is, an effect opposite or in the same direction, chemically combined with it. That is, if the herbal medicine and drug affect the same receptor or the same site, interaction occurs and a synergic or antagonistic effect may occur. While the effect of the drug increases as a result of the additive effect, the effect of the drug decreases or disappears as a result of the antagonistic effect. The concentration of the drug in body fluids, plasma, is not changed by the second drug. Although most of the drug metabolism is carried out in the liver with cytochrome P450 enzymes, the metabolism of some drugs can be in the blood, kidney, skin, and intestine. Approximately 50 different cytochrome P450 enzymes have been identified. However, a small portion of these enzymes play a role in drug metabolism. Herbal drug-drug interactions are generally pharmacokinetic-type interactions that result from enzyme inhibition or induction [12].

The following are the evaluation parameters used to determine the probability of herb-drug interactions:


**255**

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

In 2015, an estimated 422.7 million cases of cardiovascular disease (CVD) and 17.92 million CVD deaths were reported worldwide. And most people in the world still prefer complementary and alternative medicine (CAM) as their first treatment option. The consumption of over-the-counter CAM consumption increases the risk of HDI, which endangers the effective medical management of CVD. In cardiac therapy, the narrow therapeutic drug window and a wide range of cardiac drugs available for treatment are also a major cause of concern for HDI. People with chronic diseases often use CAM therapies inappropriately to manage their condition

This section of our review focuses on plants reported in the literature by preclinical or clinical studies (rats or humans) or cardiovascular drugs with appropriate case reports. These herbs are reported to affect the pharmacokinetics of some cardiovascular drugs through a variety of HDI mechanisms. Reported HDI studies of some plants commonly used for the treatment of CVDs are summarized in **Table 4** [1].

CYP3A4, CYP2D6 and CYP1A2 (inhibition)

ABCB1 C3435T genotype inhibition

(inhibition) Talinolol P-gp induction, intestinal P-gp in subjects with

(moderate inhibition)

P-gp induction

CYP3A4 (induction)

Warfarin CYP 1A2 (induction) CYP2D6, CYP3A4, and OATs (inhibition)

CYP3A4, CYP1A2, CYP2B6, CYP2C19, CYP2C9

CYP2C9 (potent inhibition) CYP2C19, CYP3A4

CYP1E1, CYP2C6, CYP2C11 (inhibition)

CYP2B6, CYP2C9, CYP2C19 (inhibition)

inhibition) CYP2C19 (induction)

**9.1. Herb-drug interactions in the treatment of cardiovascular** 

and thereby increase the potential or possibility of HDI formation [1].

**Herbs Interacting drugs CYP, P-gp induction/inhibition**

*Fucus vesiculosus* L. Amiodarone, valsartan CYP1A (induction), CYP2C9 (inhibition)

*Salvia miltiorrhiza* Bunge Warfarin CYP3A4 (induction) CYP1A2, CYP2C9,

*Allium sativum* Atorvastatin, cilostazol CYP2C9, CYP3A4 and CYP2D6 (inhibition)

Nifedipine Unknown

*Panax ginseng* Warfarin CYP3A4 (induction), CYP2C11 (inhibition)

simvastatin, lovastatin

*Citrus paradisi* Macfad. Felodipine CYP3A4 (inhibition)

*Ginkgo biloba* Diltiazem, cilostazol CYP1A2, CYP3A, and CYP2C9 (P-gp inhibition

Talinolol Intestinal P-gp inhibition

Nifedipine CYP3A4 (inhibition)

Talinolol OATP inhibition Aliskiren OATP2B1 inhibition Atorvastatin Intestinal CYP3A4 inhibition Lovastatin Intestinal CYP3A4 inhibition Simvastatin Intestinal CYP3A4 inhibition

Diltiazem CYP3A4 CYP2D6

propranolol

warfarin, clopidogrel

phenprocoumon

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

*Piper longum* L*.* Verapamil, digoxin,

*Zingiber officinale* Roscoe Nifedipine,

*Glycrrhiza glabra* Atorvastatin,

*Pueraria montana* (Lour.) Merr. var. *lobata* (Willd.) Sanjappa & Pradeep

*Terminalia bellirica* (Gaertn.) Roxb.

*Curcuma longa* L. Losartan, rosuvastatin,

**disorders (CVDs)**


*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

## **9.1. Herb-drug interactions in the treatment of cardiovascular disorders (CVDs)**

In 2015, an estimated 422.7 million cases of cardiovascular disease (CVD) and 17.92 million CVD deaths were reported worldwide. And most people in the world still prefer complementary and alternative medicine (CAM) as their first treatment option. The consumption of over-the-counter CAM consumption increases the risk of HDI, which endangers the effective medical management of CVD. In cardiac therapy, the narrow therapeutic drug window and a wide range of cardiac drugs available for treatment are also a major cause of concern for HDI. People with chronic diseases often use CAM therapies inappropriately to manage their condition and thereby increase the potential or possibility of HDI formation [1].

This section of our review focuses on plants reported in the literature by preclinical or clinical studies (rats or humans) or cardiovascular drugs with appropriate case reports. These herbs are reported to affect the pharmacokinetics of some cardiovascular drugs through a variety of HDI mechanisms. Reported HDI studies of some plants commonly used for the treatment of CVDs are summarized in **Table 4** [1].


*Medical Toxicology*

and case reports. Many mechanisms play a role in these interactions, and interactions are seen in two main types as pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic interactions result in changes in drug absorption, distribution, metabolism, and elimination. These interactions usually occur far away from the drug's effect and lead to a decrease or increase in effect as a result of the change in drug concentration in body fluids. In order to say that there is a pharmacokinetic interaction, the plasma level or half-life of the drug should be determined experimentally. Various interactions such as cytochrome P450, UDP-glucuronyl-transferase (UGTs), and carrier proteins such as P-glycoprotein (P-gp) are thought to play a role in these interactions. Pharmacokinetic interactions are the most common interactions as a cause of undesirable side effects. If the herb or natural products or its secondary metabolites inhibit an enzyme involved in drug metabolism, it may increase the potential for toxic effects, as it will reduce the metabolism of drugs that metabolize the enzyme and turn into an inactive metabolite as a result of metabolism. If the herbal drug induces an enzyme, a decrease in drug effect may be observed, since the metabolism of the drugs that are metabolized by this enzyme and converted into inactive metabolite as a result of metabolism will increase. Likewise, if the drug turns into an active metabolite as a result of metabolism, if the herbal drug induces the enzyme responsible for the metabolism of the drug, an increase in drug effect or toxic effect may be observed as a result of increased effective metabolite concentration [12].

Pharmacodynamic interactions occur when one drug changes the effect of another, that is, an effect opposite or in the same direction, chemically combined with it. That is, if the herbal medicine and drug affect the same receptor or the same site, interaction occurs and a synergic or antagonistic effect may occur. While the effect of the drug increases as a result of the additive effect, the effect of the drug decreases or disappears as a result of the antagonistic effect. The concentration of the drug in body fluids, plasma, is not changed by the second drug. Although most of the drug metabolism is carried out in the liver with cytochrome P450 enzymes, the metabolism of some drugs can be in the blood, kidney, skin, and intestine. Approximately 50 different cytochrome P450 enzymes have been identified. However, a small portion of these enzymes play a role in drug metabolism. Herbal drug-drug interactions are generally pharmaco-

kinetic-type interactions that result from enzyme inhibition or induction [12].

The following are the evaluation parameters used to determine the probability

b.Concurrent diseases, conditions, or other drugs associated with adverse events.

g.The time sequence of drug administration to adverse event is reasonable.

**254**

of herb-drug interactions:

a.Adequate patient history.

f. Chronology is complete.

c.Concomitant medications are documented.

d.The description of the interactors is sufficient.

e.Clearly, alternative explanations are excluded.

h.An adverse event has been sufficiently defined.

i. The event ends after stopping the medicine.

j. The activity repeats upon challenge again [3].


#### **Table 4.**

*Reported HDI studies of some commonly used herbs for the treatment of CVDs [1, 13].*

### **9.2 Herb-drug interactions with chemotherapeutic drugs**

One of the most important risks associated with the combined use of herbal products and chemotherapeutic agents is herb-drug interactions. Patients with chronic illnesses who use more than one drug have a higher risk. Herb-drug interaction is undesirable in the treatment of cancer due to the perpendicular dose-effect relationship and toxicity of chemotherapeutic agents. The most common mechanism of herb-drug interaction is herbal mediated inhibition and/or stimulation of drug-metabolizing enzymes and/or transport proteins that lead to changes in the pharmacokinetic order of the victim drug. This focus on clinically significant herb-drug interaction should attract public attention, including practitioners, researchers, and cancer chemotherapy consumers (**Table 5**) [14].

## **9.3 Herb-drug interactions with attention-deficit/hyperactivity disorder (ADHD) medication**

In some pediatric patients with attention deficit/hyperactivity disorder (ADHD), natural products such as herbal medicines are used. Although herbal remedies are thought to be safe when used appropriately, they may contain active ingredients that can interact with concurrently used medications and can lead to adverse events for natural products-drug interactions (**Table 6**) [15].

**257**

**Table 5.**

**medication**

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

Docetaxel Prospective study in 10 cancer patients

> patient controlled, pharmacokinetic

*Ginseng* Imatinib Case report After receiving ginseng in patients

*Grapefruit juice* Docetaxel Case report Grapefruit juice has been found to

*Milk thistle* Irinotecan Pharmacokinetic study It has been found that milk thistle

*St John's wort* Docetaxel Pharmacokinetic study St John's wort was found to cause

pharmacokinetic study

2-period, open-label, fixed sequence study

Nilotinib Open label, randomized, 2 period crossover

Irinotecan Unblinded, randomized crossover study

Imatinib Open-label, crossover

**Study type Results**

with etoposide rarely reduced platelet (16 × 103/L) compared to etoposide

Echinacea did not cause a significant change in the pharmacokinetics of

Garlic was found to reduce docetaxel clearance. Although this reduction is not statistically significant, it can potentially increase side effects due to

alone (44 × 103/L)

docetaxel accumulation

receiving imatinib for 7 years, hepatotoxicity symptoms began to appear. Hepatotoxicity improved upon

discontinuation of ginseng

half-life of docetaxel

reduce the clearance of docetaxel, while increasing the AUC and terminal

It was found that grapefruit juice increased the AUC and the peak concentration of nilotinib, but did not affect the elimination half-life

causes a statistically insignificant decrease in irinotecan clearance, which is unlikely to cause a clinical effect

a significant decrease in plasma docetaxel concentration

metabolite (SN-38)

St John's wort caused a 42% reduction in plasma concentrations of the active

St John's wort reduced the plasma concentration of imatinib by 32% and reduced the half-life of imatinib by 21%

St John's wort increased the imatinib clearance by 43% and decreased the plasma concentration by 30%

docetaxel

*Echinacea* Etoposide Case report It was found that taking echinacea

**9.4 Herb-drug interactions (HDI) with chronic kidney disease (CKD)** 

*Herbal interaction studies with chemotherapeutic agents conducted in human subjects [14].*

Chronic kidney disease (CKD) is defined as abnormalities in kidney structure or function that have been going on for more than 3 months, with adverse health consequences. The prevalence of CKD is estimated to be 8–16% worldwide.

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

**drugs**

*Garlic* Docetaxel Prospective,

**Herbs Cancer** 


*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

**Table 5.**

*Medical Toxicology*

*Camellia sinensis* (L.)

*Schisandra chinensis* (Turcz.) Baill.

*Citrus × sinensis* (L.)

*Silybum marianum* (L.)

Osbeck

Gaertn.

**Table 4.**

Kuntze.

**9.2 Herb-drug interactions with chemotherapeutic drugs**

*Reported HDI studies of some commonly used herbs for the treatment of CVDs [1, 13].*

One of the most important risks associated with the combined use of herbal products and chemotherapeutic agents is herb-drug interactions. Patients with chronic illnesses who use more than one drug have a higher risk. Herb-drug interaction is undesirable in the treatment of cancer due to the perpendicular dose-effect relationship and toxicity of chemotherapeutic agents. The most common mechanism of herb-drug interaction is herbal mediated inhibition and/or stimulation of drug-metabolizing enzymes and/or transport proteins that lead to changes in the pharmacokinetic order of the victim drug. This focus on clinically significant herb-drug interaction should attract public attention, including practitioners, researchers, and cancer chemotherapy consumers

**Herbs Interacting drugs CYP, P-gp induction/inhibition**

Digoxin P-gp induction Talinolol P-gp induction

Rosuvastatin P-gp induction

Aliskiren OATP2B1 inhibition

Aliskiren OATP2B1 inhibition

Losartan CYP2C9 inhibition

Talinolol P-gp inhibition

*Malus pumila* Mill. Atenolol Unknown (possible mediated by OATP

Phenprocoumon CYP2C9 induction, CYY3A4 induction Atorvastatin CYP3A4 induction, P-gp induction Pravastatin Intestinal CYP3A4 inhibition Simvastatin CYP3A4 induction, P-gp induction

Digoxin P-gp induction, digoxin uptake inhibition

uptake)

function and modulation of intestinal drug

Nadolol Intestinal OATP1A2 inhibition Rosuvastatin Intestinal OATP1A2/OATB2P inhibition

*Mentha × piperita* L. Felodipine CYP3A4 (inhibition) *Hypericum perforatum* Nifedipine CYP3A4 (induction) Verapamil

**9.3 Herb-drug interactions with attention-deficit/hyperactivity disorder** 

In some pediatric patients with attention deficit/hyperactivity disorder (ADHD), natural products such as herbal medicines are used. Although herbal remedies are thought to be safe when used appropriately, they may contain active ingredients that can interact with concurrently used medications and can lead to

adverse events for natural products-drug interactions (**Table 6**) [15].

**256**

(**Table 5**) [14].

**(ADHD) medication**

*Herbal interaction studies with chemotherapeutic agents conducted in human subjects [14].*

## **9.4 Herb-drug interactions (HDI) with chronic kidney disease (CKD) medication**

Chronic kidney disease (CKD) is defined as abnormalities in kidney structure or function that have been going on for more than 3 months, with adverse health consequences. The prevalence of CKD is estimated to be 8–16% worldwide.


#### **Table 6.**

*Description of adverse status reports evaluated for the cause of natural product-drug interactions [15].*

Most importantly, patients with CKD are advised to avoid over-the-counter products and herbal medicines according to the Kidney Disease Improving Global Outcome (KDIGO) guidelines. However, several studies have revealed that many patients with CKD have returned to complementary and alternative medicine (CAM) for a desperate treatment. The consumption of unregistered herbal products is more common today because these products can be easily purchased from on-line media, street markets, or stores. It is an alarming trend as it may be linked to an increase in the number of patients with liver and kidney failure in public hospitals. In addition, patients with CKD are at higher risk of developing cardiovascular disease. Most of them are prescribed with antiplatelet and anticoagulants. Anti-platelets and anticoagulants

**259**

**Table 7.**

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

may interact with synergistic or additives with CAM products, which can cause blood-thinning effects that may later cause excessive bleeding (**Table 7**) [16].

root extract, high doses, combined

(EGb 761, 80 mg/day), crude *Ginkgo* plant parts (5 ppm of toxic

day), higher doses than usual

extract administered intravenously and intraperitoneally, high-dose

Dong Quai extract (tablet), dose: 565 mg (1–2 tab/day) for 4 weeks

Fenugreek seeds, fenugreek seed

powder (>5 g)

2.25–4.5 L/day)

*Camellia sinensis* Tea (high dose >600 mg/day or

*Spirulina* A product containing blue-green algae

*The herbs used by CKD patients and their safety concerns [16].*

*Medicago sativa* L. Alfalfa seed products It may cause autoimmune diseases (SLE,

*Morinda citrifolia* L. Noni juice, dose >400 mL It may cause liver toxicity, and contains

*Andrographis paniculata* extract (50 and 100 mg/kg/ day) for 14 days, standardized *Andrographis* extract

**Safety concerns**

Cinnamon extract It may have hypoglycemic effect and may

It may hypoglycemic effect and can cause hypertension, as well as may interact with anticoagulants

It may interact with anticoagulants and can cause a severe allergic reaction

cause worsen liver conditions

and hydrochlorothiazide

in children

anticoagulants

effect of estrogen)

It may interact with anticoagulants

It may interact with anticoagulants, antihypertensive, anti-hyperlipidemic,

It may hypoglycemic effect and may interact with hypoglycemic agents, death

It may increase the risk of bleeding, increase cancer risk, as well as may interact with anticoagulants, antiplatelet, estrogen (augments the

multiple sclerosis, rheumatoid arthritis), photosensitivity, estrogen-like and hypoglycemic effects, and may interact with immunosuppressants, warfarin, oral contraceptives, estrogen conjugates, oral hypoglycemic agents, iron, vitamin

It may have a hypoglycemic and

It may cause liver problems, and may interact with nadolol (beta-blocker),

It may increase the risk of bleeding, may interact with immunosuppressant, antiplatelet, anticoagulants, NSAIDs, other herbs that reduce blood clotting (e.g., ginseng, garlic, ginkgo)

estrogen-like effects

diuretics

high potassium

It may possibly interact with

It may interact with hepatic metabolizing enzymes, anticoagulant, antiplatelet, anti-hyperglycemic, barbiturates

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

*Herbs* **Dosage form/doses associated** 

*Panax ginseng* Crude and standardized *Ginseng*

*Ginkgo biloba* Standardized *Ginkgo* extract

*Zingiber officinale* Dried root, liquid extract, doses >10 g/day

*Allium sativum* Fresh garlic, dried powder (>7 g/

*Momordica charantia* L. Bitter melon tea, bitter melon

*Punica granatum* L. Pomegranate juice, pomegranate extract

*Cinnamomum cassia* (L.) J.Presl

*Andrographis paniculata* (Burm.f.)

*Angelica sinensis* (Oliv.)

*Trigonella foenumgraecum* L.

Nees

Diels

preparation

ginkgolic acid)

dietary intake

bitter melon seed

**with safety concerns**

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

may interact with synergistic or additives with CAM products, which can cause blood-thinning effects that may later cause excessive bleeding (**Table 7**) [16].


#### **Table 7.**

*The herbs used by CKD patients and their safety concerns [16].*

*Medical Toxicology*

*Ginkgo biloba*

*Efalex evening primrose oil*

*Evening primrose oil*

*St John's wort*

**Table 6.**

**Herbs Drugs Case**

**258**

Most importantly, patients with CKD are advised to avoid over-the-counter products and herbal medicines according to the Kidney Disease Improving Global Outcome (KDIGO) guidelines. However, several studies have revealed that many patients with CKD have returned to complementary and alternative medicine (CAM) for a desperate treatment. The consumption of unregistered herbal products is more common today because these products can be easily purchased from on-line media, street markets, or stores. It is an alarming trend as it may be linked to an increase in the number of patients with liver and kidney failure in public hospitals. In addition, patients with CKD are at higher risk of developing cardiovascular disease. Most of them are prescribed with antiplatelet and anticoagulants. Anti-platelets and anticoagulants

*Description of adverse status reports evaluated for the cause of natural product-drug interactions [15].*

result was considered medically significant

Strattera An 8-year-old male patient with a history of ADHD, astigmatism,

Ritalin A 7-year-old female was treated with Ritalin 10 mg/day orally for ADHD

Concerta An 11-year-old male was using 36 mg of methylphenidate per day for ADHD for several years. The patient was also taking evening primrose oil for an unknown indication and duration. There was a history of moderate to severe developmental delay and slow learning. Methylphenidate was exhausted on December 30, 2002 and was brought to emergency with severe torticollis, rolling arm movements, lip chewing, and pharyngitis. On January 2, 2003, he presented to the pediatrician with the same symptoms and speech disorder, did not eat or drink, and was hospitalized. Torticollis improved with intravenous cetirizine hydrochloride. The patient was also diagnosed with

Concerta A 17-year-old female with a history of ADHD and depression was treated with

Ritalin A 15-year-old male started 20 mg oral/day Ritalin for ADHD in 1998 and

methylphenidate for about a year. Concurrent medication included St. John's wort. The patient experienced psychotic symptoms on an unknown day. The patient saw and heard things that were not there and disturbed at night. The

tolerated it well. He suffered a period of sadness from June 1, 2001, and he took St. John's wort (five drops) orally to treat his depression. A few hours later he presented agitation, unexplained crying, depression-changing aggression, and difficulty concentrating. On June 6, 2001, St. John's wort ceased and these symptoms subsided. Three weeks later, St. John's wort was restarted and the same symptoms appeared. St John's wort was quitted and symptoms were relieved again. The reaction was considered medically

The case was considered medically significant

related to Strattera

pharyngeal abscess

significant

behavioral disorder, learning disorder, and asthma was using 25 mg Strattera for ADHD from October 2008 to September 2009. From May 2001 to November 2010, he was taking 85 mg of *G. biloba* daily. After starting Strattera, the patient experienced headaches and eye pain resulting in hospitalization. On ophthalmological examination, suspicion of glaucoma appeared. The reporting child psychiatrist stated that the incident was

from October 2001. The patient has also been taking Efalex evening primrose oil since 2001. On March 7, 2002, she developed a tic including her both arms. It has become more complex. Ritalin was discontinued on March 7, 2002. There was an improvement in head, arm, neck, and leg movements after cessation, but movements were still present. There was no history of tic or movement disorders in the family. Before the tics, the patient had a nightmare for 1 week. She also had a skin rash and dry skin in her mouth.

## **9.5 Herb-drug interactions with menopause medication**

Herbal remedies are popular among women to relieve menopausal symptoms such as hot flashes, energy loss, depression, joint pain, and insomnia. As recently reviewed, a variety of herbs used to treat menopausal symptoms can cause herbdrug interactions (**Table 8**) [17].


**Table 8.**

*Herb-drug interactions with herbs for menopause.*

## **10. Herb-micronutrient interactions**

The ability of some foods to reduce or increase the absorption of various vitamins and minerals has been known for years. Almost half of the population regularly uses some herbal products as a dietary supplement, along with the vitamin and mineral supplements. The use of these products has increased significantly over the past two decades, and a number of clinically relevant herbal drug interactions have been identified during this time. Therefore, it is likely that the mechanisms underlying many herb-drug interactions may also affect micronutrient absorption, distribution, metabolism, and excretion. Not taking these eccentricities into account can negatively affect the outcome and interpretation of any advanced herb-micronutrient interaction studies [18] (**Table 9**).


**261**

**Table 10.**

Turkey tail mushroom

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center has developed About Herbs (www.aboutherbs.com), which provides research information, including alleged uses, side effects, and herb-drug interactions for about 284 dietary supplements. Using Google Analytics, they have detected that more than 26,317,000 hits have been recorded since November 2002. According to these data, top 10 plant and/or dietary supplements in 2018 were chaga mushrooms, turmeric, ashwagandha, reishi mushroom, graviola, Active Hexose-Correlated Compound, boswellia, dandelion, green tea, and *Coriolus versicolor*. In **Table 10**, based on the literature researches in PubMed, their scientific and common names, plant-drug interactions and their appropriate use in the oncology environment are discussed. In the past 16 years, evidence of the use of these supplements is based on limited studies and mostly preclinical findings. It is important to inform healthcare professionals about popular dietary supplements so that patients can be informed to make decisions that maximize benefits and minimize risks [19] Hereby, important

**Key interaction and** 

Antihyperglycemic agents

Increase testosterone levels

**Avoid in**

Renal disease Diabetic patients on treatment (acarbose)

Renal disease

Prostate cancer

Radiation therapy

on doxorubicin, zofran, and aromatase inhibitor

Hormone-sensitive breast cancer

Elevated liver function

immunosuppressants (in theory)

treatment

(letrozole)

tests

CYP2D6 enzyme inducer Breast cancer patients

Unknown Contact dermatitis

Unknown Patients on

**concerns**

High in oxalates Anticoagulants Anti-platelets

CYP2C9 enzyme

Anticoagulants Anti-platelets

CYP1A2 enzyme Diuretic

Antihyperglycemic agents Estrogenic activity

empty stomach can cause liver toxicity Bortezomib

in men

Graviola *Annona muricate* L. Antihyperglycemic agents Diabetic patients on

**11. Databases setup for plants/dietary supplements**

herb-drug interactions have been compiled in **Table 11**.

**the plants/dietary supplements**

Turmeric *Curcuma longa* High in oxalates

*Ganoderma lucidum* (Curtis) P.Karst.

*Correlated Compound*

Hand.-Mazz., *T. officinale* (L.) Weber ex

Green tea *Camellia sinensis* High doses or taken on an

*Trametes versicolor* (L.)

*Top 10 monographs accessed from the "about herbs" database in 2018.*

F.H.Wigg

Lloyd

ex Pers.) Pilát

**Common name Scientific name of** 

Chaga *Inonotus obliquus* (Ach.

Ashwagandha *Withania somnifera* (L.) Dunal

AHCC *Active Hexose-*

Boswellia *Boswellia serrata* Roxb. ex Colebr.

Dandelion *Taraxacum mongolicum*

Reishi mushroom

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

#### **Table 9.**

*Herb-micronutrient interactions and their mechanisms.*

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

## **11. Databases setup for plants/dietary supplements**

*Medical Toxicology*

drug interactions (**Table 8**) [17].

**Herbs HID**

**10. Herb-micronutrient interactions**

*Herb-drug interactions with herbs for menopause.*

**9.5 Herb-drug interactions with menopause medication**

*Cimicifuga racemosa* Increase the activity of antihypertensive agents

antipsychotics and anticoagulants *Trifolium pratense* L. Increase the activity of CYP3A4 and alters the metabolism of drugs

anticoagulants

drugs

**Phytochemicals Micronutrient** 

Phytic acid Calcium, iron,

*Herb-micronutrient interactions and their mechanisms.*

Herbal remedies are popular among women to relieve menopausal symptoms such as hot flashes, energy loss, depression, joint pain, and insomnia. As recently reviewed, a variety of herbs used to treat menopausal symptoms can cause herb-

*Angelica sinensis* Inhibit platelet aggregation and increase risk of bleeding if co-medicated with

*Oenothera biennis* L. Potentially interacts with anti-inflammatory drugs, corticosteroids, beta-blockers,

*Humulus lupulus* L. Interact with CNS depressants, antipsychotics, hormones and CYP-metabolized

The ability of some foods to reduce or increase the absorption of various vitamins and minerals has been known for years. Almost half of the population regularly uses some herbal products as a dietary supplement, along with the vitamin and mineral supplements. The use of these products has increased significantly over the past two decades, and a number of clinically relevant herbal drug interactions have been identified during this time. Therefore, it is likely that the mechanisms underlying many herb-drug interactions may also affect micronutrient absorption, distribution, metabolism, and excretion. Not taking these eccentricities into account can negatively affect the outcome and interpretation of any advanced herb-micronutrient interaction studies [18]

**affected**

Folate, ascorbate

zinc

Silymarins Iron They reduce absorption through

Hyperforin (St. John's wort) Vitamin D3 It enhances plasma clearance through

**Effect and interaction mechanisms**

PPs reduce absorption through uptake

It reduces absorption through complexation

induction of CYP3A4 metabolism

Iron PPs reduce absorption through complexation

transporter inhibition

complexation

**260**

**Table 9.**

(**Table 9**).

Plant polyphenols (PPs) (tea catechins, phloretin, quercetin)

**Table 8.**

The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center has developed About Herbs (www.aboutherbs.com), which provides research information, including alleged uses, side effects, and herb-drug interactions for about 284 dietary supplements. Using Google Analytics, they have detected that more than 26,317,000 hits have been recorded since November 2002. According to these data, top 10 plant and/or dietary supplements in 2018 were chaga mushrooms, turmeric, ashwagandha, reishi mushroom, graviola, Active Hexose-Correlated Compound, boswellia, dandelion, green tea, and *Coriolus versicolor*. In **Table 10**, based on the literature researches in PubMed, their scientific and common names, plant-drug interactions and their appropriate use in the oncology environment are discussed. In the past 16 years, evidence of the use of these supplements is based on limited studies and mostly preclinical findings. It is important to inform healthcare professionals about popular dietary supplements so that patients can be informed to make decisions that maximize benefits and minimize risks [19] Hereby, important herb-drug interactions have been compiled in **Table 11**.


#### **Table 10.**

*Top 10 monographs accessed from the "about herbs" database in 2018.*


**263**

**Plants** *Ginkgo biloba*

**Effect and usage**

To improve cognitive functions, cerebrovascular disorders and vertigo [20]

Ibuprofen (NSAID)

Anticoagulant (warfarin) and antiplatelet (aspirin) drugs

Antidepressant (trazodone)

Thiazide diuretic (not specified in the original paper)

Nicardipine (a calcium channel blocker)

Nifedipine, diltiazem (calcium channel blockers) and talinolol (β-blocker)

Cyclosporine Midazolam (benzodiazepine)

Propranolol (β-blocker)

Theophylline Omeprazole (proton pump inhibitor)

Tolbutamide (an antidiabetic drug)

Amikacin (aminoglycoside)

Prednisolone (corticosteroid)

Hydrocortisone (corticosteroid)

Dexamethasone (corticosteroid)

Antihypertensives

*Glycyrrhiza glabra*

Expectorant, antispasmodic and antiinflammatory properties and in treatment

of peptic and duodenal ulcers [20]

Further increase in blood pressure [39]

Decreasing the hypotensive activity of drugs [40]

Possible increased antihypertensive activity resulting from high bioavailability [41–44]

Decreased bioavailability of drug [45]

Decreased bioavailability of drug [46]

Decreased the plasma concentrations of propranolol [47]

Less efficacy with *Ginkgo* [48]

May induce the metabolism, and reduce the effect of

May increase or decrease the hypoglycemic effect of

tolbutamide [50]

Amikacin ototoxicity may enhance [51]

Glycyrrhizin increases the plasma concentrations and

potentiates pharmacological effects of prednisolone [52, 53]

Glycyrrhetinic acid potentiates the activity the topical

cutaneous vasoconstrictor effect [54]

Dexamethasone induces the mineralocorticoid effects of

Mineralocorticoid effects (sodium and water retention

and hypokalemia) of plant reduce the efficacy of the

drugs that use to lower blood pressure. Hypokalemic

effect of the plant may increase the effect of the loop and

thiazide diuretics [20]

glycyrrhizin [55]

omeprazole [49]

**Drugs** Phenobarbital

**Interactions** Reduces the therapeutic potency of phenobarbital [35]

May cause fatal intracerebral bleeding [36]

Possible additive inhibition on platelet aggregation [37, 38]

*Ginkgo* flavonoids increase the production of 1-(m-chlorophenyl) piperazine (mCPP), an active metabolite of trazodone. Flavonoids and mCPP may induce the enhancement of GABAergic activity [34]

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

*DOI: http://dx.doi.org/10.5772/intechopen.92040*


*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

*Medical Toxicology*

**262**

**Plants** *Allium sativum*

**Effect and usage**

Antihypertensive, antithrombotic,

fibrinolytic, antimicrobial, antidiabetic and

lipid-lowering properties [20]

**Drugs** Anticoagulant Antiretroviral (saquinavir)

Antidiabetic (metformin, chlorpropamide)

Paracetamol (acetaminophen)

*Aloe vera* L.

Laxative antidiabetic [20]

Corticosteroids and potassium-depleting diuretics

Cardiac glycosides and antiarrhythmic drugs

Antidiabetics

*Cassia senna* L.

*Echinacea purpurea* (L.)

As immunostimulant and in treatment of

upper respiratory tract infections [20]

Moench.

Laxative [20]

[29, 30]

[26, 27]

**Interactions**

May lead to increased anticoagulation effect of warfarin

and may increase the risk of bleeding [21–23]

May decrease the plasma level of protease inhibitor

saquinavir [24, 25]

May occur greater reduction in blood glucose level

May change some pharmacokinetic variables of

paracetamol [28]

Laxative and potassium lowering effect may result in

hypokalemia [29, 30]

May enhance the hypokalemia-related arrhythmia

Because of the glucose-lowering effects, diabetic patients

should be careful when combining with an antidiabetic

agent [31]

Corticosteroids and potassium-depleting diuretics

Digitalis glycosides

Anabolic steroids, amiodarone (antiaritmic), methotrexate

(chemotherapy agent-immunosuppressant), ketoconazole

(antifungal), and acetaminophen

Immunosuppressants

Midazolam (benzodiazepine)

May lead to hypokalemia, since senna can cause

excessive water and potassium loss, theoretically [20]

Risk of digitalis toxicity due to hypokalemic effect of

senna, theoretically [20]

The risk of hepatoxicity by concomitant usage of

potentially hepatoxic *Echinacea* [32, 33]

Might decrease the effects of immunosuppressants,

May increase oral bioavailability of midazolam or [20]

theoretically [34]


**265**

**Plants** *Panax ginseng*

**Effect and usage**

Adaptogenic [20]

**Drugs** Phenelzine (MAO inhibitor)

Warfarin (anticoagulant)

Warfarin, heparin, aspirin, and NSAIDs

Caffeine Barbiturates and benzodiazepines

Alprazolam (benzodiazepine)

Levodopa Acetaminophen

Barbiturates

*Valeriana officinalis*

anxiolytic [20]

Used for stress and insomnia as sedative and

*Piper methysticum*

Anxiolytic, sedative, aphrodisiac

**Interactions** Additive nervous system effect of drug such as headache, tremor, sleeplessness and mania [34]

INR may decrease by concomitant usage [71]

There is no clear data, but due to the antiplatelet components in *P. ginseng*, it should be avoided concomitant using [32]

Possible additive stimulant effects [20]

Might potentiate the effects of central nervous system depressants [72]

Risk of coma due to possible additive effect on GABA receptor [72]

May reduce the efficacy due to possible dopaminergic antagonism [73]

May enhance the risk of hepatotoxicity [33]

Excessive sedation. The active component valerenic

acid seems to likely to have the additive effect to

phenobarbital [74]

Possible additive sedative effects [20]

Possible reverse effect to the sedative effect of Valerian

May reduce the platelet aggregation and enhance the

bleeding tendency [33]

May potentiate the antiplatelet effects [76]

May increase the bioavailability [77]

May reduce the blood glucose level [26]

[20]

Other central nervous system depressants such as

benzodiazepines and opioids

Caffeine

*Zingiber officinale*

To reduce nausea and emesis induced

NSAIDs Nifedipine Metronidazole Glibenclamide (antidiabetic)

by pregnancy, chemotherapy, and

postoperative ileus [75]

**Table 11.** *Some herb-drug interactions.*

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

*DOI: http://dx.doi.org/10.5772/intechopen.92040*


*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

> **Table 11.** *Some herb-drug interactions.*

*Medical Toxicology*

**264**

**Plants** *Hypericum perforatum*

**Effect and usage**

To treat depression, seasonal affective

disorder, anxiety and insomnia, especially

related to menopause [20]

**Drugs** Gliclazide (an antidiabetic drug)

Carbamazepine, phenytoin and phenobarbital

(antiepileptics)

Alprazolam, midazolam, triazolam and quazepam

(benzodiazepines)

Indinavir (protease inhibitor)

Nevirapine (nonnucleoside reverse transcriptase)

Cyclosporine, tacrolimus, (Immunosuppressants)

Warfarin and phenprocoumon (anticoagulants)

Simvastatin and atorvastatin (antihyperlipidemic agents)

Nifedipine, verapamil (calcium channel blockers) and

talinolol (a β-adrenoceptor blocker)

Oral contraceptives

Carbamazepine (antiepileptic)

Sertraline, nefazodone (selective serotonin reuptake

inhibitors)

Anticoagulant or antiplatelet drugs

*Linum usitatissimum* L.

Demulcent for bronchitis and coughs, and

topically used for burns [20]

cholesterol [63, 64]

May decrease the bioavailability of drugs [65]

Associated with increased metabolism of ethinyl

estradiol, norethindrone, and ketodesogestrel, and may

cause bleeding and unwanted pregnancy [66–69]

Should be considered a mild interaction between

carbamazepine and *Hypericum*

May be occurred the symptoms of central serotonergic

In the view of the thought that omega-3 fatty acids such

as linolenic acid have antiplatelet effects, should be

concerned about the possibility of prolonged bleeding [20]

syndrome [70]

May observe the increasing serum level of total

**Interactions**

Increases the apparent clearance of gliclazide [56]

Clinically significant interaction is unlikely, but

*Hypericum* should be used carefully with these

antiepileptic drugs [20]

Since the main compound hyperforin induces the

enzyme CYP3A4, bioavailability may decrease [20, 57]

May decrease the antiretroviral drugs and may lead to

development of drug resistance [58, 59]

May decrease the blood levels and may lead the acute

organ rejection in transplant patients [60–62]

May cause a moderate reduction in the anticoagulant

effects of the drugs [20]

## **12. Criteria for risk assessment of herbal products**

There have been an increasing number of herbal products as food ingredients or supplements, which are a commercially important part of the health food market. Herbal products can range from whole foods (e.g., cranberry against urinary infections) to pharmaceutical-like preparations in unit dose form, such as tablets, capsules, or drops, and are thought to provide additional benefits beyond basic nutrition. The regulatory position on food supplements is uncertain (food or medicine?), and there is concern about the safety assurance of these products. Several cases of poisoning have been reported with herbal products. In some cases, these were caused by contamination with other plant species, but this is not always the case. In addition, toxic components (e.g., pyrrolizidine alkaloids) are accumulated at different concentrations in different parts of the source plant, and climatic and agronomic differences lead to great variability in the composition [78].

Therefore, it is not possible to provide a simple checklist of suitable tests to ensure the safety of herbal products. International guidelines are available for the safety assessment of herbal product and should be designed to cover all life stages to ensure a lifelong intake that can be consumed without significant health risk [78].

Information relating to herbal product identification, characterization, and standardization:


**267**

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

adverse effects reports, and contraindications [78].

**13. Possible ways to reduce the toxic effects of herbal products**

**K.** Preclinical and clinical studies. Clinical data including variability of response,

Natural products/compounds are unique remedies, but as Paracelsus (1493– 1541) stated that all substances are poison and this is just the correct dose that makes them medicine. There are some rules in the literature that can be summa-

a.If the herbal remedy is not prescribed by a registered physician, it should be

b.The label and expiration date of the herbal products should be checked for the

d.Herbal products should not be used with drugs possessing narrow therapeutic

e.Herbal products containing heavy metals such as arsenic, lead, and mercury

f. Pregnant or breastfeeding mothers should be careful when using herbal remedies such as black cohosh, chamomile, sage, Dong Quai root, feverfew, ginger,

g.Excessive consumption of herbal/herbal medicine/natural products should be

Herbal and traditional medicines are preferred as primary health care by three

quarters of the world's population. Therefore, it is crucial in drug research to investigate the effectiveness and adverse effects of herbal medicine, to identify the active compounds in medicinal plants and to detect contamination from poisonous plants or herbal mixtures. In 2013, the World Health Organization (WHO) published the WHO traditional medicine strategy (2014–2023). It aims to support the use of Traditional Medicine (TM) and/or Complementary and Alternative Medicine (CAM) to improve public health, including phytotherapy using of medicinal product (MP) and/or herbal medicinal product (HMP) for medical practice. The plan aims to increase the safety, efficacy, and quality of TM and/or CAM by expanding its knowledge base and providing guidance on regulatory and quality assurance standards (WHO, 2013). In 2016, the National Complementary and Integrative Health Center (NCCIH) published a strategic plan to explore complementary

c.If the herbal medicine is consumed with allopathic medicines, the doctor

index such as cyclosporin, digoxin, theophylline, and warfarin.

avoided and dosing instructions should be followed [3].

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

**I.** Bioavailability of active principles.

**J.** Toxicological assessment.

rized as follows:

considered unsafe.

should be informed.

should not be used.

**14. Conclusion**

kava kava, St. John's wort, etc.

seal of the regulatory authority.

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*


*Medical Toxicology*

standardization:

studies).

**12. Criteria for risk assessment of herbal products**

agronomic differences lead to great variability in the composition [78].

Therefore, it is not possible to provide a simple checklist of suitable tests to ensure the safety of herbal products. International guidelines are available for the safety assessment of herbal product and should be designed to cover all life stages to ensure a lifelong intake that can be consumed without significant health risk [78]. Information relating to herbal product identification, characterization, and

**A.** Botanical source: identity to family (geographic origin), genus, and species of source plant (with authority), and, if relevant, variety and chemotype; common names as well as part(s) of plant used. Evidence from previous human exposure through food or other sources (ethnobotanical and folk medicine

**B.** Growing conditions: wild or cultivated plant (Good Agricultural Practice—GAP), site and time of harvest; stage of growth at harvest, post-harvest treatment (drying, fermentation, etc.), storage conditions, phytosanitary measures pre- and postharvest (including use of and limits for pesticides) are very important.

standard reference (e.g., herbal Pharmacopoeias), identity tests (macroscopic, microscopic, FT-IR, TLC, GC, HPLC, etc.), quantitative tests (especially

**D.** Process applied to starting material: preparation steps (e.g., separation, extraction processes, solvents), methods used, handling specific precautions; e.g.,

**E.** Botanical preparation: standardization criteria (markers: active constituents, other related components; plant extract ratio), specifications: levels and range for markers, physico-chemical properties of relevant components; stability, purity criteria by chain control or analysis; microbiological, mycotoxins, pesticides, and environmental contaminants. Nature and level of excipients; formulation methodology, storage conditions should have been specified.

**H.** Extent of use and estimated intake (posology and method of administration).

**C.** Raw material (fresh or dried plant materials): specifications according to

constituents related for efficacy and/or toxicity).

light/temperature sensitivity, oxidation, etc.

**F.** End product: formulated product.

**G.** Specification of the product.

There have been an increasing number of herbal products as food ingredients or supplements, which are a commercially important part of the health food market. Herbal products can range from whole foods (e.g., cranberry against urinary infections) to pharmaceutical-like preparations in unit dose form, such as tablets, capsules, or drops, and are thought to provide additional benefits beyond basic nutrition. The regulatory position on food supplements is uncertain (food or medicine?), and there is concern about the safety assurance of these products. Several cases of poisoning have been reported with herbal products. In some cases, these were caused by contamination with other plant species, but this is not always the case. In addition, toxic components (e.g., pyrrolizidine alkaloids) are accumulated at different concentrations in different parts of the source plant, and climatic and

**266**

**K.** Preclinical and clinical studies. Clinical data including variability of response, adverse effects reports, and contraindications [78].

## **13. Possible ways to reduce the toxic effects of herbal products**

Natural products/compounds are unique remedies, but as Paracelsus (1493– 1541) stated that all substances are poison and this is just the correct dose that makes them medicine. There are some rules in the literature that can be summarized as follows:


## **14. Conclusion**

Herbal and traditional medicines are preferred as primary health care by three quarters of the world's population. Therefore, it is crucial in drug research to investigate the effectiveness and adverse effects of herbal medicine, to identify the active compounds in medicinal plants and to detect contamination from poisonous plants or herbal mixtures. In 2013, the World Health Organization (WHO) published the WHO traditional medicine strategy (2014–2023). It aims to support the use of Traditional Medicine (TM) and/or Complementary and Alternative Medicine (CAM) to improve public health, including phytotherapy using of medicinal product (MP) and/or herbal medicinal product (HMP) for medical practice. The plan aims to increase the safety, efficacy, and quality of TM and/or CAM by expanding its knowledge base and providing guidance on regulatory and quality assurance standards (WHO, 2013). In 2016, the National Complementary and Integrative Health Center (NCCIH) published a strategic plan to explore complementary

and integrative health science. This plan has been published to inform the public, healthcare professionals, and health policy makers, with evidence-based information about the usefulness and safety of complementary and integrative health interventions and their role in health care development. The plan uses key research to facilitate understanding of the biological effects, mechanisms of action, effectiveness, and clinical effects of complementary health approaches. Both the WHO and NCCIH plans aim to improve TM and CAM knowledge, including phytotherapy. Therefore, understanding herb-drug interactions and the molecular mechanisms involved in these processes is a way to guarantee safe use of MP and/or HMP. In addition, this can help therapeutic planning and healthcare professionals to recommend the best treatment strategy to use.

In this review, some critical issues are also discussed. The botanical identification and labeling of the plant material are important for preventing undesirable health problems. The changes in the scientific definitions of the plants in traditional medicine in time can cause unwanted or toxicologic effects by the usage of the wrong plant. The contamination of the plants with the environmental contaminants (microorganisms, fungal toxins such as aflatoxins, pesticides, and heavy metals), inappropriate preparation process, and interaction of traditional herbs by concomitant or consecutive usage also endanger the safety of herbal medicine for human health. What makes herbal medicine research valuable is that it has the chance to research harmful and toxic plants for developing pharmacologically and therapeutically worth remedies, and to develop medicinal plant combinations as safe and efficient herbal medicines. Standardization and strict control mechanisms are essential to maintain the high quality of herbal products and to prevent from the contaminations for the safety of patients [17].

The following guidelines can be suggested to minimalize the risk of herbal uses:


Do not believe it is useless if it is natural or it is harmless if it is natural [79].

## **Conflict of interest**

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this chapter.

**269**

**Author details**

Ankara, Turkey

Cigdem Kahraman1

University, Ankara, Turkey

, Zekiye Ceren Arituluk<sup>2</sup>

\*Address all correspondence to: itatli@hacettepe.edu.tr

provided the original work is properly cited.

1 Faculty of Pharmacy, Department of Pharmacognosy, Hacettepe University,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Faculty of Pharmacy, Department of Pharmaceutical Botany, Hacettepe

and Iffet Irem Tatli Cankaya<sup>2</sup>

\*

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

## **Author details**

*Medical Toxicology*

and integrative health science. This plan has been published to inform the public, healthcare professionals, and health policy makers, with evidence-based information about the usefulness and safety of complementary and integrative health interventions and their role in health care development. The plan uses key research to facilitate understanding of the biological effects, mechanisms of action, effectiveness, and clinical effects of complementary health approaches. Both the WHO and NCCIH plans aim to improve TM and CAM knowledge, including phytotherapy. Therefore, understanding herb-drug interactions and the molecular mechanisms involved in these processes is a way to guarantee safe use of MP and/or HMP. In addition, this can help therapeutic planning and healthcare professionals to

In this review, some critical issues are also discussed. The botanical identification and labeling of the plant material are important for preventing undesirable health problems. The changes in the scientific definitions of the plants in traditional medicine in time can cause unwanted or toxicologic effects by the usage of the wrong plant. The contamination of the plants with the environmental contaminants (microorganisms, fungal toxins such as aflatoxins, pesticides, and heavy metals), inappropriate preparation process, and interaction of traditional herbs by concomitant or consecutive usage also endanger the safety of herbal medicine for human health. What makes herbal medicine research valuable is that it has the chance to research harmful and toxic plants for developing pharmacologically and therapeutically worth remedies, and to develop medicinal plant combinations as safe and efficient herbal medicines. Standardization and strict control mechanisms are essential to maintain the high quality of herbal products and to prevent from the

The following guidelines can be suggested to minimalize the risk of herbal uses:

1.Should not be used in case of pregnancy or a possibility of pregnancy and to

4.Should be bought from the pharmacies and only in case the plant names are

Do not believe it is useless if it is natural or it is harmless if it is natural [79].

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in

stated on the packages and sealed by the Ministry of Health.

recommend the best treatment strategy to use.

contaminations for the safety of patients [17].

2.Should not be used when breast-feeding.

3.Should not be used as daily and in large amounts.

babies.

**Conflict of interest**

this chapter.

**268**

Cigdem Kahraman1 , Zekiye Ceren Arituluk<sup>2</sup> and Iffet Irem Tatli Cankaya<sup>2</sup> \*

1 Faculty of Pharmacy, Department of Pharmacognosy, Hacettepe University, Ankara, Turkey

2 Faculty of Pharmacy, Department of Pharmaceutical Botany, Hacettepe University, Ankara, Turkey

\*Address all correspondence to: itatli@hacettepe.edu.tr

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[47] Zhao LZ, Huang M, Chen J, Ee PL, Chan E, Duan W, et al. Induction of propranolol metabolism by Ginkgo biloba extract EGb 761 in rats. Current Drug Metabolism. 2006;**7**(6):577-587. DOI: 10.2174/138920006778017740

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[47] Zhao LZ, Huang M, Chen J, Ee PL, Chan E, Duan W, et al. Induction of propranolol metabolism by Ginkgo biloba extract EGb 761 in rats. Current Drug Metabolism. 2006;**7**(6):577-587. DOI: 10.2174/138920006778017740

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[57] Borrelli F, Izzo AA. Herb-drug interactions with St John's wort (*Hypericum perforatum*): An update on clinical observations. American Association of Pharmaceutical Scientists Journal. 2009;**11**(4):710-727. DOI: 10.1208/s12248-009-9146-8

[58] Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St John's wort. Lancet. 2000;**355**(9203):547-548. DOI: 10.1016/S0140-6736(99)05712-8

[59] de Maat MMR, Hoetelmans RMW, Mathôt RAA, van Gorp ECM, Meenhorst PL, Mulder JW, et al. Drug interaction between St John's wort and nevirapine. AIDS. 2001;**15**(3):420-421

[60] Moschella C, Jaber BL. Interaction between cyclosporine and *Hypericum perforatum* (St. John's wort) after organ transplantation. American Journal of Kidney Diseases. 2001;**38**(5):1105-1107. DOI: 10.1053/ajkd.2001.28617

[61] Hebert MF, Park JM, Chen YL, Akhtar S, Larson AM. Effects of St. John's wort (*Hypericum perforatum*) on tacrolimus pharmacokinetics in healthy volunteers. Journal of Clinical Pharmacology. 2004;**44**(1):89-94. DOI: 10.1177/0091270003261078

[62] Mai I, Störmer E, Bauer S, Krüger H, Budde K, Roots I. Impact of St John's wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients. Nephrology Dialysis Transplantation. 2003;**18**(4):819-822. DOI: 10.1093/ndt/ gfg002

[63] Andrén L, Andreasson A, Eggertsen R. Interaction between a commercially available St John's Wort product (Movina) and atorvastatin in patients with hypercholesterolemia. European Journal of Clinical Pharmacology. 2007;**63**:913-916. DOI: 10.1007/s00228-007-0345-x

[64] Sugimoto K, Ohmori M, Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, et al. Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin. Clinical Pharmacology and Therapeutics. 2001;**70**(6):518-524. DOI: 10.1067/ mcp.2001.120025

[65] Di YM, Li CG, Xue CC, Zhou SF. Clinical drugs that interact with St. John's wort and implication in drug development. Current Pharmaceutical Design. 2008;**14**(17):1723-1742. DOI: 10.2174/138161208784746798

[66] Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John's Wort with oral contraceptives: Effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception. 2005;**71**(6):402-408. DOI: 10.1016/j. contraception.2004.11.004

[67] Hall SD, Wang Z, Huang SM, Hamman MA, Vasavada N, Adigun AQ, et al. The interaction between St John's wort and an oral contraceptive. Clinical Pharmacology and Therapeutics. 2003;**74**(6):525-535. DOI: 10.1016/j. clpt.2003.08.009

[68] Pfrunder A, Schiesser M, Gerber S, Haschke M, Bitzer J, Drewe J. Interaction of St John's wort with lowdose oral contraceptive therapy: A randomized controlled trial. British Journal of Clinical Pharmacology. 2003;**56**(6):683-690. DOI: 10.1046/j.1365-2125.2003.02005.x

[69] Schwarz UI, Büschel B, Kirch W. Unwanted pregnancy on self-medication with St. John's wort

**275**

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

Chinese Medicine. 2006;**34**(4):545-551. DOI: 10.1142/s0192415x06004089

Obonga WO. Herb-drug interaction: A case study of effect of ginger on the pharmacokinetic of metronidazole in rabbit. Indian Journal of Pharmaceutical Sciences. 2008;**70**(2):230-232. DOI:

[77] Okonta JM, Uboh M,

10.4103/0250-474X.41462

toxlet.2004.03.001

[78] Walker R. Criteria for risk assessment of botanical food supplements. Toxicology Letters. 2004;**149**(1):187-195. DOI: 10.1016/j.

[79] Huxtable RJ. The myth of

beneficent nature: The risks of herbal preparations. Annals of Internal Medicine. 1992;**117**(2):165-166. DOI: 10.7326/0003-4819-117-2-165

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

Pharmacology. 2003;**55**(1):112-113. DOI:

despite hormonal contraception. British Journal of Clinical

10.1046/j.1365-2125.2003.01716.x

[70] Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant drug interactions in the elderly. Journal of Geriatric Psychiatry and Neurology. 1999;**12**(1):7-10. DOI:

10.1177/089198879901200103

and pharmacodynamic drug interactions with kava (*Piper methysticum* Forst. f.). Journal of Ethnopharmacology. 2004;**93**(2):153- 160. DOI: 10.1016/j.jep.2004.04.009

[73] Shi S, Klotz U. Drug

10.1055/s-2007-969384

Clinical Pharmacokinetics. 2012;**51**(2):77-104. DOI:

interactions with herbal medicines.

10.2165/11597910-000000000-00000

[74] Hendriks H, Bos R, Woerdenbag HJ, Koster AS. Central nervous depressant activity of valerenic acid in the mouse. Planta Medica. 1985;**51**(1):28-31. DOI:

[75] Lien H-C, Sun WM, Chen Y-H, Kim H, Hasler W, Owyang C. Effects of ginger on motion sickness and gastric slow-wave dysrhythmias induced by circular vection. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2003;**284**(3):G481-G4G9. DOI: 10.1152/ajpgi.00164.2002

[76] Young HY, Liao JC, Chang YS, Luo YL, Lu MC, Peng WH. Synergistic effect of ginger and nifedipine on human platelet aggregation: A study in hypertensive patients and normal volunteers. The American Journal of

aph.10031

[71] Vaes LPJ, Chyka PA. Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: Nature of the evidence. The Annals of Pharmacotherapy. 2000;**34**(12):1478-1482. DOI: 10.1345/

[72] Anke J, Ramzan I. Pharmacokinetic

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

despite hormonal contraception. British Journal of Clinical Pharmacology. 2003;**55**(1):112-113. DOI: 10.1046/j.1365-2125.2003.01716.x

*Medical Toxicology*

sj.bjp.0707685

genotype on the pharmacokinetics and pharmacodynamics of gliclazide. British Journal of Pharmacology. 2008;**153**(7):1579-1586. DOI: 10.1038/ product (Movina) and atorvastatin in patients with hypercholesterolemia. European Journal of Clinical

Pharmacology. 2007;**63**:913-916. DOI:

Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, et al. Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin. Clinical Pharmacology and Therapeutics. 2001;**70**(6):518-524. DOI: 10.1067/

10.1007/s00228-007-0345-x

[64] Sugimoto K, Ohmori M,

[65] Di YM, Li CG, Xue CC,

Zhou SF. Clinical drugs that interact with St. John's wort and implication in drug development. Current Pharmaceutical Design. 2008;**14**(17):1723-1742. DOI: 10.2174/138161208784746798

[66] Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John's Wort with oral contraceptives: Effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and

breakthrough bleeding. Contraception. 2005;**71**(6):402-408. DOI: 10.1016/j.

contraception.2004.11.004

clpt.2003.08.009

[67] Hall SD, Wang Z, Huang SM, Hamman MA, Vasavada N, Adigun AQ, et al. The interaction between St John's wort and an oral contraceptive. Clinical Pharmacology and Therapeutics. 2003;**74**(6):525-535. DOI: 10.1016/j.

[68] Pfrunder A, Schiesser M,

2003;**56**(6):683-690. DOI: 10.1046/j.1365-2125.2003.02005.x

[69] Schwarz UI, Büschel B, Kirch W. Unwanted pregnancy on self-medication with St. John's wort

Gerber S, Haschke M, Bitzer J, Drewe J. Interaction of St John's wort with lowdose oral contraceptive therapy: A randomized controlled trial. British Journal of Clinical Pharmacology.

mcp.2001.120025

[57] Borrelli F, Izzo AA. Herb-drug interactions with St John's wort (*Hypericum perforatum*): An update on clinical observations. American Association of Pharmaceutical Scientists Journal. 2009;**11**(4):710-727. DOI: 10.1208/s12248-009-9146-8

[58] Piscitelli SC, Burstein AH,

Mathôt RAA, van Gorp ECM,

DOI: 10.1053/ajkd.2001.28617

10.1177/0091270003261078

of tacrolimus and mycophenolic acid in renal transplant patients. Nephrology Dialysis Transplantation. 2003;**18**(4):819-822. DOI: 10.1093/ndt/

[63] Andrén L, Andreasson A, Eggertsen R. Interaction between a commercially available St John's Wort

[61] Hebert MF, Park JM, Chen YL, Akhtar S, Larson AM. Effects of St. John's wort (*Hypericum perforatum*) on tacrolimus pharmacokinetics in healthy volunteers. Journal of Clinical Pharmacology. 2004;**44**(1):89-94. DOI:

[62] Mai I, Störmer E, Bauer S, Krüger H, Budde K, Roots I. Impact of St John's wort treatment on the pharmacokinetics

Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St John's wort. Lancet. 2000;**355**(9203):547-548. DOI: 10.1016/S0140-6736(99)05712-8

[59] de Maat MMR, Hoetelmans RMW,

Meenhorst PL, Mulder JW, et al. Drug interaction between St John's wort and nevirapine. AIDS. 2001;**15**(3):420-421

[60] Moschella C, Jaber BL. Interaction between cyclosporine and *Hypericum perforatum* (St. John's wort) after organ transplantation. American Journal of Kidney Diseases. 2001;**38**(5):1105-1107.

**274**

gfg002

[70] Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant drug interactions in the elderly. Journal of Geriatric Psychiatry and Neurology. 1999;**12**(1):7-10. DOI: 10.1177/089198879901200103

[71] Vaes LPJ, Chyka PA. Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: Nature of the evidence. The Annals of Pharmacotherapy. 2000;**34**(12):1478-1482. DOI: 10.1345/ aph.10031

[72] Anke J, Ramzan I. Pharmacokinetic and pharmacodynamic drug interactions with kava (*Piper methysticum* Forst. f.). Journal of Ethnopharmacology. 2004;**93**(2):153- 160. DOI: 10.1016/j.jep.2004.04.009

[73] Shi S, Klotz U. Drug interactions with herbal medicines. Clinical Pharmacokinetics. 2012;**51**(2):77-104. DOI: 10.2165/11597910-000000000-00000

[74] Hendriks H, Bos R, Woerdenbag HJ, Koster AS. Central nervous depressant activity of valerenic acid in the mouse. Planta Medica. 1985;**51**(1):28-31. DOI: 10.1055/s-2007-969384

[75] Lien H-C, Sun WM, Chen Y-H, Kim H, Hasler W, Owyang C. Effects of ginger on motion sickness and gastric slow-wave dysrhythmias induced by circular vection. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2003;**284**(3):G481-G4G9. DOI: 10.1152/ajpgi.00164.2002

[76] Young HY, Liao JC, Chang YS, Luo YL, Lu MC, Peng WH. Synergistic effect of ginger and nifedipine on human platelet aggregation: A study in hypertensive patients and normal volunteers. The American Journal of

Chinese Medicine. 2006;**34**(4):545-551. DOI: 10.1142/s0192415x06004089

[77] Okonta JM, Uboh M, Obonga WO. Herb-drug interaction: A case study of effect of ginger on the pharmacokinetic of metronidazole in rabbit. Indian Journal of Pharmaceutical Sciences. 2008;**70**(2):230-232. DOI: 10.4103/0250-474X.41462

[78] Walker R. Criteria for risk assessment of botanical food supplements. Toxicology Letters. 2004;**149**(1):187-195. DOI: 10.1016/j. toxlet.2004.03.001

[79] Huxtable RJ. The myth of beneficent nature: The risks of herbal preparations. Annals of Internal Medicine. 1992;**117**(2):165-166. DOI: 10.7326/0003-4819-117-2-165

**Chapter 14**

**Abstract**

**1. Introduction**

**277**

Analgesic Poisoning

oxycodone, in addition to poisoning signs and treatments.

**Keywords:** fentanyl, acetaminophen, paracetamol, oxycodone, intoxication

Poisoning is a medical emergency representing a major health problem worldwide, and the rate of poisoning of both prescription and over-the-counter (OTC) drugs is increasing day by day [1]. According to the American Association of Poison Control Centers (AAPCC) 2018 Annual Report, the most common cause of drug poisonings was analgesics in all human exposures [2]. Analgesics are used to manage mild, moderate, and severe, as well as acute and chronic, pain [3]. Generally, opioid and non-opioid drugs are used for analgesia [3]. According to the AAPCC 2018 Annual Report, most frequent causes of analgesic poisoning are fentanyl, acetaminophen, and oxycodone, respectively [2]. Fentanyl and oxycodone are opioid analgesics, whereas acetaminophen is a non-opioid analgesic [3].

Opioids are potent analgesics, but their use is limited as they cause addiction, withdrawal, and tolerance [4]. Opioids exert their effects by stimulating classical opioid receptors [μ (mu), δ (delta), and κ (kappa)] that are widely distributed in the body [5, 6]. These receptors show seven transmembrane domain structures specific to G-protein-coupled receptors, are induced by morphine and antagonized by naloxone (NLX), and had similar analgesic effect [4]. According to the studies, μ receptor was also related with addiction [7]. Opioid addiction develops in both psychic and physical dependence [4]. After physical dependence development, opioid consumption is maintained to prevent withdrawal symptoms [4]. Treatment

According to the 2018 Annual Report of the American Association of Poison Control Centers (AAPCC), published in 2019, the most common cause of poisoning was medicines in all human exposures. According to the data in this report, the most common group of drugs that cause poisoning in humans are analgesics. The first three drugs that cause poisoning among analgesics are fentanyl, acetaminophen, and oxycodone, respectively. Fentanyl and oxycodone are analgesic drugs with an opioid nature. Opioid analgesics are the drugs of choice for acute and chronic pain management, but after repeated exposure, they cause addiction as a result of stimulation in the brain reward center, are used in higher doses to achieve the same effect, and lead to withdrawal syndrome when medication is not taken. Acetaminophen, which takes the second place in analgesic-related poisoning, is a non-opioid analgesic and antipyretic drug. Acetaminophen is often found in hundreds of over-the-counter (OTC) medications. In addition to being an OTC drug, acetaminophen often causes poisoning as it is cheap and easily accessible. This chapter reviews pharmacological properties of fentanyl, acetaminophen, and

*Mahluga Jafarova Demirkapu*

## **Chapter 14** Analgesic Poisoning

*Mahluga Jafarova Demirkapu*

## **Abstract**

According to the 2018 Annual Report of the American Association of Poison Control Centers (AAPCC), published in 2019, the most common cause of poisoning was medicines in all human exposures. According to the data in this report, the most common group of drugs that cause poisoning in humans are analgesics. The first three drugs that cause poisoning among analgesics are fentanyl, acetaminophen, and oxycodone, respectively. Fentanyl and oxycodone are analgesic drugs with an opioid nature. Opioid analgesics are the drugs of choice for acute and chronic pain management, but after repeated exposure, they cause addiction as a result of stimulation in the brain reward center, are used in higher doses to achieve the same effect, and lead to withdrawal syndrome when medication is not taken. Acetaminophen, which takes the second place in analgesic-related poisoning, is a non-opioid analgesic and antipyretic drug. Acetaminophen is often found in hundreds of over-the-counter (OTC) medications. In addition to being an OTC drug, acetaminophen often causes poisoning as it is cheap and easily accessible. This chapter reviews pharmacological properties of fentanyl, acetaminophen, and oxycodone, in addition to poisoning signs and treatments.

**Keywords:** fentanyl, acetaminophen, paracetamol, oxycodone, intoxication

## **1. Introduction**

Poisoning is a medical emergency representing a major health problem worldwide, and the rate of poisoning of both prescription and over-the-counter (OTC) drugs is increasing day by day [1]. According to the American Association of Poison Control Centers (AAPCC) 2018 Annual Report, the most common cause of drug poisonings was analgesics in all human exposures [2]. Analgesics are used to manage mild, moderate, and severe, as well as acute and chronic, pain [3]. Generally, opioid and non-opioid drugs are used for analgesia [3]. According to the AAPCC 2018 Annual Report, most frequent causes of analgesic poisoning are fentanyl, acetaminophen, and oxycodone, respectively [2]. Fentanyl and oxycodone are opioid analgesics, whereas acetaminophen is a non-opioid analgesic [3].

Opioids are potent analgesics, but their use is limited as they cause addiction, withdrawal, and tolerance [4]. Opioids exert their effects by stimulating classical opioid receptors [μ (mu), δ (delta), and κ (kappa)] that are widely distributed in the body [5, 6]. These receptors show seven transmembrane domain structures specific to G-protein-coupled receptors, are induced by morphine and antagonized by naloxone (NLX), and had similar analgesic effect [4]. According to the studies, μ receptor was also related with addiction [7]. Opioid addiction develops in both psychic and physical dependence [4]. After physical dependence development, opioid consumption is maintained to prevent withdrawal symptoms [4]. Treatment of opioid addiction is long and difficult. For this purpose, opioid agonists, such as methadone and buprenorphine, an opioid antagonist naltrexone, or abstinencebased treatment may be preferred [8]. This disease, referred to as "opioid abuse and opioid dependence" in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSMIV-TR), has been changed to "opioid use disorder" in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [9].

**2. Analgesics that often lead to poisoning**

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

N-[1-(2-phenylethyl)piperidin-4-yl]propanamide.

**PDs and PKs Routes of administration**

Half-life elimination 15–25 h Adults: 2–4 h

Excretion • Urine (primarily) • Feces

*PDs and PKs of fentanyl at therapeutic doses [16, 21–23].*

**Table 2.**

**279**

International Union of Pure and Applied Chemistry (IUPAC) name: N-phenyl-

Adverse effects (**Table 3**) occur when serum fentanyl concentration rises above 2 ng/mL [16]. CNS depression occurs above 3 ng/mL, whereas profound respiratory

Since it is an opioid drug, fentanyl has the potential for abuse [4]. As mentioned above, with repeated use of fentanyl, tolerance develops, which allows higher doses to achieve the same effect [4]. Therefore, fentanyl can be administered at toxic doses when abused. In addition, toxicity may develop with fentanyl used for therapeutic purposes [2]. These usually occur after accidental ingestion, following use in opioid non-tolerant patients and improper dosing [2]. Known and expected adverse reactions occur more severely, whether administered for abuse or therapeutic purposes [16]. The most important of these is respiratory depression, which can have fatal consequences. Concomitant use of fentanyl with drugs inhibiting CYP3A4 (e.g., erythromycin, ketoconazole, voriconazole, ritonavir) may cause potentially fatal respiratory depression (**Table 4**). Fentanyl may be associated with the development of serotonin syndrome. This risk increases when used concomitantly with

**Intranasal i.m. i.v. Transdermal patch Transmucosal**

Onset of action 5–10 min 7–8 min Immediately 6 h 5–15 min Duration — 1–2 h 0.5–1 h 72–96 h — Absorption — —— 12–24 h Rapidly Distribution — — 4 L/kg — 25.4 L/kg

> • n-Dealkylation to *norfentanyl* (active metabolite) • Amide hydrolyzation to *despropionylfentanyl* • Alkyl hydroxylation to *hydroxyfentanyl*

Bioavailability 64% 50–76%

Children: 2.4–36 h

20–27 h 3–14 h

Protein binding Alpha-1-acid glycoprotein (mainly), albumin, and erythrocytes Metabolism In the liver (primarily via CYP3A4) and intestinal mucosa

depression usually occurs at concentrations of 10 to 20 ng/mL [16].

Fentanyl is a synthetic and lipophilic phenylpiperidine opioid agonist with molecular formula C22H28N20 and a molecular weight of 336.5 g/mol [16]. Fentanyl, 100 times more potent than morphine, was developed in the 1950s and approved by the FDA in 1968 [17]. Fentanyl is used for pain management, induction and maintenance of general anesthesia, recovery from general or regional anesthesia, and analgesia and sedation in intensive care unit patients [18–20]. It is applied by injection (i.v., i.m., epidural, intrathecal), transdermal (device and patch), transmucosal (buccal film and tablet, sublingual spray and tablet, lozenge), and intranasal means [16]. Pharmacodynamics and pharmacokinetics are summarized

**2.1 Fentanyl**

*Analgesic Poisoning*

in **Table 2**.

Classical opioid receptors are distributed in the peripheral tissue as well as central nervous system (CNS) [4]. Stimulation of these receptors in the central nervous system results in analgesia, drowsiness, euphoria, a sense of detachment, respiratory depression, nausea and vomiting, depressed cough reflex, and hypothermia [4]. When these receptors are stimulated in peripheral tissues, miosis, orthostatic hypotension, constipation, urinary retention, etc. emerge [4]. After stimulation of these Gi/0-coupled opioid receptors, the adenylate cyclase enzyme is suppressed, and the level of cyclic AMP decreases [4]. In addition, the voltage-gated calcium channels in the axon ends or neuron soma are closed, and intracellular calcium levels are reduced, and potassium channels are opened, leading to an increase in potassium conductance [4]. As a result, inhibition and hyperpolarization of neurons occur when opioid receptors are stimulated [10, 11]. Analgesic or antinociceptive effects, which are indicated for use of opioids, develop at the level of the brain and spinal cord [12]. At the brain level, attenuation of impulse spread is weakened and the perception of pain is inhibited, and at the spinal cord level, the transmission of pain impulses is suppressed [12].

Non-opioid or non-steroidal anti-inflammatory drugs (NSAIDs) are used to manage mild and moderate pain, as well as to reduce fever [13]. Although NSAIDs exact mechanism of action has not been fully established, according to the previous studies, it inhibits the cyclooxygenase pathways, which are involved in prostaglandin synthesis [14]. Prostaglandins are responsible for eliciting pain sensations [14]. NSAIDs do not cause addiction and withdrawal like opioid analgesics, and tolerance to analgesic effect does not develop [13].

Poisoning may lead to more dangerous consequences when taking more than one medication [2]. It is due to pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions (DDIs). According to Lexicomp, there are five DDI types (**Table 1**), which are clinically important (X, D, and C) and insignificant (B and A) [15].


#### **Table 1.** *DDI types and treatment approach [15].*

## **2. Analgesics that often lead to poisoning**

## **2.1 Fentanyl**

of opioid addiction is long and difficult. For this purpose, opioid agonists, such as methadone and buprenorphine, an opioid antagonist naltrexone, or abstinencebased treatment may be preferred [8]. This disease, referred to as "opioid abuse and opioid dependence" in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSMIV-TR), has been changed to "opioid use disorder" in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

Classical opioid receptors are distributed in the peripheral tissue as well as central nervous system (CNS) [4]. Stimulation of these receptors in the central nervous system results in analgesia, drowsiness, euphoria, a sense of detachment, respiratory depression, nausea and vomiting, depressed cough reflex, and hypothermia [4]. When these receptors are stimulated in peripheral tissues, miosis, orthostatic hypotension, constipation, urinary retention, etc. emerge [4]. After stimulation of these Gi/0-coupled opioid receptors, the adenylate cyclase enzyme is suppressed, and the level of cyclic AMP decreases [4]. In addition, the voltage-gated calcium channels in the axon ends or neuron soma are closed, and intracellular calcium levels are reduced, and potassium channels are opened, leading to an increase in potassium conductance [4]. As a result, inhibition and hyperpolarization of neurons occur when opioid receptors are stimulated [10, 11]. Analgesic or antinociceptive effects, which are indicated for use of opioids, develop at the level of the brain and spinal cord [12]. At the brain level, attenuation of impulse spread is weakened and the perception of pain is inhibited, and at the spinal cord level, the

Non-opioid or non-steroidal anti-inflammatory drugs (NSAIDs) are used to manage mild and moderate pain, as well as to reduce fever [13]. Although NSAIDs exact mechanism of action has not been fully established, according to the previous studies, it inhibits the cyclooxygenase pathways, which are involved in prostaglandin synthesis [14]. Prostaglandins are responsible for eliciting pain sensations [14]. NSAIDs do not cause addiction and withdrawal like opioid analgesics, and tolerance

Poisoning may lead to more dangerous consequences when taking more than one medication [2]. It is due to pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions (DDIs). According to Lexicomp, there are five DDI types (**Table 1**), which are clinically important (X, D, and C) and insignificant

X Avoid combination The risks associated with simultaneous use of this drug outweigh the

C Monitor therapy The benefits associated with simultaneous use of this drug outweigh the

No intervention required

benefits. Simultaneous use of this drug is contraindicated

The rate of benefit and risk due to simultaneous use of this drug needs to be evaluated, and aggressive monitoring of the patient, empirical dosage changes, or selection of alternative agents should be considered

risks, and dosage adjustments of one or both drugs may be considered

transmission of pain impulses is suppressed [12].

to analgesic effect does not develop [13].

**Approach Explanation**

B No action needed No intervention required

(B and A) [15].

D Consider therapy modification

A No known interaction

*DDI types and treatment approach [15].*

**Table 1.**

**278**

**DDI types**

(DSM-5) [9].

*Medical Toxicology*

International Union of Pure and Applied Chemistry (IUPAC) name: N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide.

Fentanyl is a synthetic and lipophilic phenylpiperidine opioid agonist with molecular formula C22H28N20 and a molecular weight of 336.5 g/mol [16]. Fentanyl, 100 times more potent than morphine, was developed in the 1950s and approved by the FDA in 1968 [17]. Fentanyl is used for pain management, induction and maintenance of general anesthesia, recovery from general or regional anesthesia, and analgesia and sedation in intensive care unit patients [18–20]. It is applied by injection (i.v., i.m., epidural, intrathecal), transdermal (device and patch), transmucosal (buccal film and tablet, sublingual spray and tablet, lozenge), and intranasal means [16]. Pharmacodynamics and pharmacokinetics are summarized in **Table 2**.

Adverse effects (**Table 3**) occur when serum fentanyl concentration rises above 2 ng/mL [16]. CNS depression occurs above 3 ng/mL, whereas profound respiratory depression usually occurs at concentrations of 10 to 20 ng/mL [16].

Since it is an opioid drug, fentanyl has the potential for abuse [4]. As mentioned above, with repeated use of fentanyl, tolerance develops, which allows higher doses to achieve the same effect [4]. Therefore, fentanyl can be administered at toxic doses when abused. In addition, toxicity may develop with fentanyl used for therapeutic purposes [2]. These usually occur after accidental ingestion, following use in opioid non-tolerant patients and improper dosing [2]. Known and expected adverse reactions occur more severely, whether administered for abuse or therapeutic purposes [16]. The most important of these is respiratory depression, which can have fatal consequences. Concomitant use of fentanyl with drugs inhibiting CYP3A4 (e.g., erythromycin, ketoconazole, voriconazole, ritonavir) may cause potentially fatal respiratory depression (**Table 4**). Fentanyl may be associated with the development of serotonin syndrome. This risk increases when used concomitantly with


#### **Table 2.** *PDs and PKs of fentanyl at therapeutic doses [16, 21–23].*


#### **Table 3.**

*Common adverse reactions of fentanyl [16, 21–26].*

drugs at risk of serotonin syndrome (**Table 4**). Population that are particularly at risk and need attention are children; geriatric, cachectic, or debilitated patients; and patients with renal and hepatic impairment, underlying pulmonary conditions, known or suspected paralytic ileus and gastrointestinal obstruction, mucositis (sublingual spray), and cardiac bradyarrhythmias [16]. Clinically important DDIs are summarized in **Table 4**.

> management and reduction of fever [27]. Acetaminophen is often found in hundreds of OTC and prescription medicines [28]. PDs and PKs are summarized in

— — SSRI

Constipation Eluxadoline — Anticholinergic agents,

— — Anticholinergic agents

Fexinidazole Ceritinib, siponimod Bradycardia-causing agents,

**Possible effects Clinically important DDI types**

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

Azelastine, bromperidol, orphenadrine, oxomemazine, paraldehyde, thalidomide, mifepristone

Dapoxetine, monoamine oxidase inhibitors (MAOI)

Increase in the CNS depressant effects

*Analgesic Poisoning*

Enhancement in the serotonergic effects and serotonin syndrome

**XD C**

Blonanserin, chlormethiazole, CNS depressants, droperidol, flunitrazepam,

moderate)

lemborexant, meperidine, methotrimeprazine, opioid agonists, oxycodone, perampanel,

Ethanol, alizapride, dimethindene,

brimonidine, bromopride, tetrahydrocannabinol, cannabidiol, *Cannabis*, chlorphenesin carbamate, dronabinol, lisuride, lofexidine, magnesium sulfate, metoclopramide, minocycline (systemic), nabilone, piribedil, pramipexole, ropinirole, rotigotine, rufinamide

Almotriptan, alosetron, amphetamines, antiemetics (5HT3 antagonists), dexmethylphenidatemethylphenidate, dextromethorphan, eletriptan, ergot derivatives, buspirone, lorcaserin, ondansetron, oxitriptan, ramosetron, selective serotonin reuptake inhibitors (SSRI), serotonin 5-HT1D receptor agonists (triptans), serotonin/ norepinephrine reuptake inhibitors (SNRI), St John's

wort, Syrian rue

ivabradine, lacosamide, midodrine, ruxolitinib, succinylcholine, terlipressin, tofacitinib

ramosetron

phenobarbital, primidone, sodium oxybate, suvorexant, zolpidem, tramadol, tricyclic antidepressants (TCA), CYP3A4 inhibitors (strong,

Linezolid, meperidine, methylene blue, nefazodone, ozanimod, tramadol, TCA

95% of acetaminophen undergoes biotransformation, while 5% is excreted unchanged into the urine [29]. Approximately 45–55% of acetaminophen transforms into glucuronide conjugates via UDP-glucuronosyltransferase, 30–35% into sulfate conjugates via sulfotransferase, and only 5% into toxic metabolite NAPQI

**Table 5**.

**281**

**Table 4.**

Urinary retention

Enhancement in the bradycardia effects

Enhancement in the psychomotor impairment

*Fentanyl and clinically important DDIs [15].*

## **2.2 Acetaminophen**

IUPAC name: N-(4-hydroxyphenyl)acetamide

Acetaminophen is an NSAID with molecular formula C8H9NO2 and a molecular weight of 151.16 g/mol and approved by the FDA in 1951 [27]. Acetaminophen is used by oral, injection (i.v.), and rectal means for mild to moderate pain


#### **Table 4.**

drugs at risk of serotonin syndrome (**Table 4**). Population that are particularly at risk and need attention are children; geriatric, cachectic, or debilitated patients; and patients with renal and hepatic impairment, underlying pulmonary conditions, known or suspected paralytic ileus and gastrointestinal obstruction, mucositis (sublingual spray), and cardiac bradyarrhythmias [16]. Clinically important DDIs

CNS Confusion, dizziness, drowsiness, fatigue, headache, sedation, abnormal dreams,

Respiratory Dyspnea, atelectasis, cough, epistaxis, hemoptysis, flu-like symptoms,

pneumonia, nasal discomfort, postnasal drip, rhinorrhea Cardiovascular Arrhythmia, pulmonary embolism (intranasal), chest pain, palpitations, deep

Hepatic Ascites, increased serum alkaline phosphatase, increased serum AST, jaundice

Ophthalmic Blepharoptosis, blurred vision, diplopia, strabismus, swelling and drying of eye,

Dermatologic Alopecia, cellulitis, decubitus ulcer, diaphoresis, erythema, hyperhidrosis, night

abnormal gait, abnormality in thinking, agitation, altered sense of smell, amnesia, anxiety, ataxia, chills, depression, disorientation, euphoria,

hallucination, hypertonia, hypoesthesia, hypothermia, insomnia, irritability, lack of concentration, lethargy, malaise, mental status changes, neuropathy, paranoia, paresthesia, restlessness, speech disturbance, stupor, vertigo,

wheezing, hyperventilation/hypoventilation, pharyngolaryngeal pain, rhinitis, sinusitis, nasopharyngitis, pharyngitis, laryngitis, bronchitis, asthma,

vein thrombosis, hypertension/hypotension, myocardial infarction, edema

Renal failure, urinary retention, dysuria, erectile dysfunction, mastalgia, urinary incontinence, urinary tract infection, urinary urgency, vaginal hemorrhage,

Anemia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy

Dehydration, hot flash, hypercalcemia/hypocalcemia, hypokalemia,

hypomagnesemia, hyponatremia, hypoalbuminemia, hyperglycemia, weight loss

Asthenia, arthralgia, back pain, lower limb cramp, limb pain, myalgia, tremor

Constipation, nausea, vomiting, abdominal distention, abdominal pain, anorexia, decreased appetite, diarrhea, dysgeusia, dyspepsia, flatulence, gingivitis, glossitis, stomatitis, tongue disease, xerostomia, gastroesophageal reflux, gastritis, gastroenteritis, hemorrhage, ulcer, hematemesis, intestinal

Acetaminophen is an NSAID with molecular formula C8H9NO2 and a molecular weight of 151.16 g/mol and approved by the FDA in 1951 [27]. Acetaminophen is

used by oral, injection (i.v.), and rectal means for mild to moderate pain

are summarized in **Table 4**.

**Systems Symptoms**

*Medical Toxicology*

Gastrointestinal

Genitourinary (GU)

Hematologic and oncologic

Endocrine and metabolic

skeletal

**Table 3.**

**280**

Neuromuscular and

(GI)

withdrawal syndrome

obstruction, rectal pain

vaginitis

visual disturbance

Miscellaneous Hypersensitivity reaction, fever, abscess

*Common adverse reactions of fentanyl [16, 21–26].*

sweats, pallor, pruritus, skin rash

IUPAC name: N-(4-hydroxyphenyl)acetamide

**2.2 Acetaminophen**

*Fentanyl and clinically important DDIs [15].*

management and reduction of fever [27]. Acetaminophen is often found in hundreds of OTC and prescription medicines [28]. PDs and PKs are summarized in **Table 5**.

95% of acetaminophen undergoes biotransformation, while 5% is excreted unchanged into the urine [29]. Approximately 45–55% of acetaminophen transforms into glucuronide conjugates via UDP-glucuronosyltransferase, 30–35% into sulfate conjugates via sulfotransferase, and only 5% into toxic metabolite NAPQI


even death [29, 35, 36]. Additional mechanisms such as mitochondrial injury, oxy-

IUPAC name: (4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one

Respiratory Atelectasis, hypoxia, pleural effusion, pulmonary edema, stridor, wheezing

Hypocalcemia, hyponatremia, hypokalemia, hypomagnesemia,

hyperuricemia, hyperglycemia, hypervolemia

hypophosphatemia, hyperchloremia, low bicarbonate levels, hypoalbuminemia,

CNS Trismus, fatigue, headache, agitation, anxiety, insomnia

GI Constipation, nausea, vomiting, abdominal pain, diarrhea Hepatic Increased serum transaminases, hyperbilirubinemia GU Nephrotoxicity, hyperammonemia, oliguria

Cardiovascular Tachycardia, hypertension/hypotension, edema

Muscle spasm, limb pain

Mild to moderate elevations in serum aminotransferase (aspartate aminotransferase, alanine aminotransferase) levels are the first sign of liver damage; sometimes it can even occur in chronic treatment at the maximum daily dose [35, 36]. These elevations are generally asymptomatic and resolve rapidly with stopping therapy or reducing the dosage [35] and most commonly arise after taking more than 7.5 g as a single overdose [38]. If hepatotoxicity is not too severe, serum aminotransferase levels fall promptly, and recovery is rapid [39]. Instances of unintentional overdose in children are often due to errors in calculating the correct dosage or use of adult-sized tablets instead of child or infant formulations [39]. Concomitant use of acetaminophen (single) and acetaminophen-containing (combined) products may also cause toxicity [39]. Acetaminophen overdose may be manifested by renal tubular necrosis, hypoglycemic coma, and thrombocytopenia [39]. Acetaminophen has been associated with a risk of rare but serious skin reactions. These are Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, and they can be fatal [39, 40]. Population that are particularly at risk and need attention are children, since they have less glucuronidation capacity of the drug than adults, and patients with alcoholism, hepatic impairment or active hepatic disease, chronic malnutrition, severe hypovolemia, and severe renal impairment [29, 38]. Adverse reactions and clinically important DDIs of acetaminophen are summarized in **Tables 6** and **7**,

gen, and nitrogen stress deepen hepatic cell damage [37].

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

respectively.

**2.3 Oxycodone**

*Analgesic Poisoning*

**Systems Symptoms**

Ophthalmic Periorbital edema

Dermatologic Pruritus, skin rash

Anemia

Miscellaneous Hypersensitivity reaction, fever

*Common adverse reactions of acetaminophen [29, 38, 39].*

Hematologic and oncologic

Endocrine and metabolic

skeletal

**Table 6.**

**283**

Neuromuscular and

#### **Table 5.**

*PDs and PKs of acetaminophen at therapeutic doses [29–31].*

#### **Figure 1.**

*Metabolism of acetaminophen. NAPQI, N-acetyl-p-benzoquinone imine; (1) UDP-glucuronosyltransferase (1-9, 1-6, 1-1, and 2B15 isoforms); (2) CYP2E1; (3) sulfotransferase (1A1 and 1A3/1A4 isoforms) and bile salt sulfotransferase; (4) glutathione S-transferase (P and theta-1 isoforms) [33–35].*

through the CYP2E1 (**Figure 1**) [32–34]. NAPQI, produced in small amounts in therapeutic dose intakes, and hepatic glutathione are immediately transformed into nontoxic cysteine and mercapturate metabolites via glutathione S-transferase and excreted into the urine [34]. With intakes above the maximum daily dose (4 g in adults and 75 mg/kg in children), the increased formation of NAPQI depletes hepatic glutathione, covalently binds to critical cellular proteins and other vital molecules, and thereby causes acute liver toxicity (hepatic damage, liver failure) or even death [29, 35, 36]. Additional mechanisms such as mitochondrial injury, oxygen, and nitrogen stress deepen hepatic cell damage [37].

Mild to moderate elevations in serum aminotransferase (aspartate aminotransferase, alanine aminotransferase) levels are the first sign of liver damage; sometimes it can even occur in chronic treatment at the maximum daily dose [35, 36]. These elevations are generally asymptomatic and resolve rapidly with stopping therapy or reducing the dosage [35] and most commonly arise after taking more than 7.5 g as a single overdose [38]. If hepatotoxicity is not too severe, serum aminotransferase levels fall promptly, and recovery is rapid [39]. Instances of unintentional overdose in children are often due to errors in calculating the correct dosage or use of adult-sized tablets instead of child or infant formulations [39]. Concomitant use of acetaminophen (single) and acetaminophen-containing (combined) products may also cause toxicity [39]. Acetaminophen overdose may be manifested by renal tubular necrosis, hypoglycemic coma, and thrombocytopenia [39]. Acetaminophen has been associated with a risk of rare but serious skin reactions. These are Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, and they can be fatal [39, 40]. Population that are particularly at risk and need attention are children, since they have less glucuronidation capacity of the drug than adults, and patients with alcoholism, hepatic impairment or active hepatic disease, chronic malnutrition, severe hypovolemia, and severe renal impairment [29, 38]. Adverse reactions and clinically important DDIs of acetaminophen are summarized in **Tables 6** and **7**, respectively.

## **2.3 Oxycodone**

IUPAC name: (4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one


#### **Table 6.**

*Common adverse reactions of acetaminophen [29, 38, 39].*

through the CYP2E1 (**Figure 1**) [32–34]. NAPQI, produced in small amounts in therapeutic dose intakes, and hepatic glutathione are immediately transformed into nontoxic cysteine and mercapturate metabolites via glutathione S-transferase and excreted into the urine [34]. With intakes above the maximum daily dose (4 g in adults and 75 mg/kg in children), the increased formation of NAPQI depletes hepatic glutathione, covalently binds to critical cellular proteins and other vital molecules, and thereby causes acute liver toxicity (hepatic damage, liver failure) or

*salt sulfotransferase; (4) glutathione S-transferase (P and theta-1 isoforms) [33–35].*

*Metabolism of acetaminophen. NAPQI, N-acetyl-p-benzoquinone imine; (1) UDP-glucuronosyltransferase (1-9, 1-6, 1-1, and 2B15 isoforms); (2) CYP2E1; (3) sulfotransferase (1A1 and 1A3/1A4 isoforms) and bile*

**PDs and PKs Routes of administration**

Distribution Adults: 4–6 L/kg

Protein binding 10–25% Metabolism In the liver

*Medical Toxicology*

Bioavailability 88%

**Table 5.**

**Figure 1.**

**282**

Half-life elimination Adults: 2–3 h

Excretion Urine (mainly)

**Oral i.v.**

• Metabolism to glucuronide and sulfate conjugates (primarily)

By CYP2E1 to toxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI,

Onset of action Above 1 h 5–10 min Duration 4–6 h 4–6 h

Absorption Small intestine (primarily) and stomach

Children: 5–30 L/kg

**Figure 1**)

*PDs and PKs of acetaminophen at therapeutic doses [29–31].*

Children: 4–10 h


about 0.93 mg/L in a single-drug administration and 1.55 mg/L in the combined drug administration, it is fatal [51]. Common adverse reactions are summarized in

CNS Dizziness, drowsiness, headache, fatigue, abnormal dreams, twitching,

Respiratory Dyspnea, cough, epistaxis, flu-like symptoms, oropharyngeal pain, rhinitis, sinusitis, pharyngitis, laryngismus, pulmonary disease Cardiovascular Flushing, tachycardia, palpitations, cardiac failure, deep vein thrombosis,

GI Constipation, nausea, vomiting, hiccups, upper abdominal pain, abdominal pain,

gastroesophageal reflux, gastritis, gastroenteritis

Dermatologic Pruritus, diaphoresis, hyperhidrosis, skin rash, skin photosensitivity,

arthritis, laryngospasm, pathological fracture

Miscellaneous Hypersensitivity reaction, fever, infection, sepsis, seroma, accidental injury

hypertension/hypotension, edema

Hepatic Increased serum alanine aminotransferase GU Urinary retention, dysuria, urinary tract infection

excoriation, urticaria

Ophthalmic Blurred vision, amblyopia

*Common adverse reactions of oxycodone [45–47].*

Hematologic and oncologic

Endocrine and metabolic

skeletal

**Table 9.**

**285**

Neuromuscular and

abnormality in thinking, agitation, anxiety, chills, depression, hypertonia, hypoesthesia, insomnia, irritability, confusion, lethargy, nervousness, paresthesia, neuralgia, personality disorder, withdrawal syndrome

anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, xerostomia,

Anemia, leukopenia, neutropenia, thrombocytopenia, hemorrhage

Hypochloremia, hyponatremia, hyperglycemia, weight loss, gout

Asthenia, arthralgia, ostealgia, back pain, neck pain, limb pain, myalgia, tremor,

Since oxycodone is an opioid drug, like fentanyl, it has the potential for abuse and develops tolerance. Repeated use of oxycodone causes the development of tolerance, which can lead to overdose and death [45–47]. Serious, life-threatening, or fatal respiratory depression may occur with use of oxycodone orally [45]. Accidental ingestion of even one dose of oxycodone preparations by children can result in death [47]. Long-term use during pregnancy can result in neonatal opioid withdrawal syndrome [45]. Concomitant use of oxycodone with CYP3A4 inducers (e.g., carbamazepine, phenytoin, and rifampin) may result in increasing clearance and decreasing plasma concentrations of oxycodone, with possible lack in therapeutic effectiveness [45]. Concomitant use of oxycodone with CYP3A4 inhibitors may result in reduced clearance and increased plasma concentrations of oxycodone, possibly resulting in increased or prolonged opiate effects, including an increased risk of fatal respiratory depression [52]. These effects could be more pronounced with concomitant use of oxycodone and inhibitors of both CYP2D6 and CYP3A4 [52]. Population that are particularly at risk and need attention are children; geriatric, cachectic, or debilitated patients; and patients with renal and hepatic impairment, underlying pulmonary conditions, and significant genetic variability in CYP2D6 activity [45, 53]. There is no evidence to prove hepatotoxicity when used alone, whereas oxycodone-acetaminophen and other opioid-acetaminophen combinations can lead to acute liver damage caused by unintentional overdose with acetaminophen [54]. Clinically important DDIs are summarized in **Table 10**.

**Table 9**.

*Analgesic Poisoning*

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

**Systems Symptoms**

#### **Table 7.**

*Acetaminophen and clinically important DDIs [15].*

Oxycodone is a semisynthetic opioid agonist, produced from thebaine and codeine found in the raw *Papaver somniferum L*. plant and approved by the FDA in 1968, with molecular formula C18H21NO4 and a molecular weight of 315.4 g/mol [41–43]. It is used alone or in combination with acetaminophen in the management of moderate to severe pain [3]. It binds to classical opioid receptors such as fentanyl and mediates similar mechanisms of action [6]. Oxycodone also inhibits the release of vasopressin, somatostatin, insulin, and glucagon and nociceptive neurotransmitters, such as substance P, GABA, dopamine, acetylcholine, and noradrenaline [44]. The analgesic effects of oxycodone are mediated by both itself and its active metabolites, noroxycodone, oxymorphone, and noroxymorphone [21]. It can be applied both orally and rectally. PDs and PKs are summarized in **Table 8**.

Toxic effects occur when the serum oxycodone concentration is approximately 0.69 mg/L in single oxycodone administration and 0.72 mg/L in the oxycodonecombined drug administration [50]. When the serum oxycodone concentration is


#### **Table 8.**

*PDs and PKs of oxycodone at therapeutic doses [21, 45–49].*

### *Analgesic Poisoning DOI: http://dx.doi.org/10.5772/intechopen.92941*

about 0.93 mg/L in a single-drug administration and 1.55 mg/L in the combined drug administration, it is fatal [51]. Common adverse reactions are summarized in **Table 9**.

Since oxycodone is an opioid drug, like fentanyl, it has the potential for abuse and develops tolerance. Repeated use of oxycodone causes the development of tolerance, which can lead to overdose and death [45–47]. Serious, life-threatening, or fatal respiratory depression may occur with use of oxycodone orally [45]. Accidental ingestion of even one dose of oxycodone preparations by children can result in death [47]. Long-term use during pregnancy can result in neonatal opioid withdrawal syndrome [45]. Concomitant use of oxycodone with CYP3A4 inducers (e.g., carbamazepine, phenytoin, and rifampin) may result in increasing clearance and decreasing plasma concentrations of oxycodone, with possible lack in therapeutic effectiveness [45]. Concomitant use of oxycodone with CYP3A4 inhibitors may result in reduced clearance and increased plasma concentrations of oxycodone, possibly resulting in increased or prolonged opiate effects, including an increased risk of fatal respiratory depression [52]. These effects could be more pronounced with concomitant use of oxycodone and inhibitors of both CYP2D6 and CYP3A4 [52]. Population that are particularly at risk and need attention are children; geriatric, cachectic, or debilitated patients; and patients with renal and hepatic impairment, underlying pulmonary conditions, and significant genetic variability in CYP2D6 activity [45, 53]. There is no evidence to prove hepatotoxicity when used alone, whereas oxycodone-acetaminophen and other opioid-acetaminophen combinations can lead to acute liver damage caused by unintentional overdose with acetaminophen [54]. Clinically important DDIs are summarized in **Table 10**.


#### **Table 9.**

*Common adverse reactions of oxycodone [45–47].*

Oxycodone is a semisynthetic opioid agonist, produced from thebaine and codeine found in the raw *Papaver somniferum L*. plant and approved by the FDA in 1968, with molecular formula C18H21NO4 and a molecular weight of 315.4 g/mol [41–43]. It is used alone or in combination with acetaminophen in the management of moderate to severe pain [3]. It binds to classical opioid receptors such as fentanyl and mediates similar mechanisms of action [6]. Oxycodone also inhibits the release of vasopressin, somatostatin, insulin, and glucagon and nociceptive neurotransmitters, such as substance P, GABA, dopamine, acetylcholine, and noradrenaline [44]. The analgesic effects of oxycodone are mediated by both itself and its active metabolites, noroxycodone, oxymorphone, and noroxymorphone [21]. It can be applied both orally and rectally. PDs and PKs are summarized in **Table 8**.

metyrapone Methemoglobinemia — — Dapsone, local anesthetics, nitric oxide, prilocaine, sodium nitrite

Ethanol, barbiturates, carbamazepine, imatinib, mipomersen, fosphenytoin-phenytoin, isoniazid,

**Possible effects Clinically important DDI types**

Hepatotoxicity — Dasatinib,

*Acetaminophen and clinically important DDIs [15].*

**PDs and PKs Oral administration**

Distribution Adults: 2.6 L/kg

Protein binding 38–45%

Metabolism In the liver

Bioavailability 60–87%

**Table 8.**

**284**

Excretion Urine (mainly)

*PDs and PKs of oxycodone at therapeutic doses [21, 45–49].*

Onset of action 10–15 min — Duration 3–6 h ≤12 h

Children: 2.1 L/kg

noroxycodol

Half-life elimination 3.2–4 h 4.5–5.6 h

High anion gap metabolic acidosis

*Medical Toxicology*

**Table 7.**

Enhancement in the anticoagulant effects **X D C**

— — Flucloxacillin

— — Vitamin K antagonists

sorafenib, probenecid

Toxic effects occur when the serum oxycodone concentration is approximately 0.69 mg/L in single oxycodone administration and 0.72 mg/L in the oxycodonecombined drug administration [50]. When the serum oxycodone concentration is

**Immediate release Extended release**

• Albumin (primarily) and alpha-1-acid glycoprotein

• By CYP3A4 and CYP3A5 to noroxycodone and then by CYP2D6 to

oxymorphol 6-keto-reduced to alpha and beta oxycodol

• By CYP2D6 to oxymorphone and then by CYP3A4 to noroxymorphone (active). Oxymorphone (active) can also be reduced to alpha or beta

noroxymorphone. Noroxycodone (active) can also be reduced to alpha or beta


**Drugs Clinical manifestations**

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

*Analgesic Poisoning*

and death

asymptomatic Stage II (24 to 72 h):

Stage III (72 to 96 h):

system failure)

**Table 12.**

**Management steps**

**Decontamination**

**Basic measures and treatment**

**Antidotal therapy dosing**

**287**

• GI • Patch Stage IV (4 days to 2 weeks):

• Regression in symptoms and recovery phase

*Clinical manifestations of fentanyl, acetaminophen, and oxycodone poisoning [16, 61, 64–71].*

**ABC** Secure airway, breathing, and circulation as necessary

1. Ensure adequate ventilation

until ventilation is adequate 3. Require supplemental oxygen,

• Adult: 50 g orally

• Must be removed

is present

2 mg i.v. Children:

Adults:

Oxycodone Respiratory depression, sleepiness, stupor, coma, skeletal muscle flaccidity, cold

partial or complete airway obstruction, atypical snoring, and death

**Fentanyl Oxycodone Acetaminophen**

Activated charcoal: within 4 h of ingestion, unless contraindicated

1. Poisoning severity following an acute ingestion is quantified by plotting a timed serum acetaminophen concentration on the modified Rumack-Matthew nomogram 2. Antidotal therapy with N-acetyl cysteine (NAC)

**Oral dosing:** 140 mg/kg loading dose, followed by 17 doses of 70 mg/kg every 4 h **21 h i.v. protocol**: 150 mg/kg loading dose over 60 min, followed by 50 mg/kg infused over 4 h, with the final 100 mg/kg infused over the remaining 16 h • INR <2: 21 h i.v. protocol • INR >2: 21 h i.v. protocol, followed by a continuous i.v. NAC infusion at 6.25 mg/kg/h

until INR is <2

Children: 1 g/kg orally or by nasogastric tube, max. 50 g

2. Apply antidotal therapy with NLX. With a total of 5 to 10 mg, repeat administration

endotracheal intubation, and positive endexpiratory pressure, if response is inadequate to NLX or if pulmonary edema

• O2 saturation is <90%: 0.05 mg i.v. or i.m. • For apneic patients: 0.2 to 1 mg i.v. or i.m. • Patients in cardiorespiratory arrest: min.

• <20 kg: 0.1 mg/kg i.v. or intraosseous (i.

Adolescents suspected of opioid addiction: • 0.04 to 0.4 mg per dose repeated every 3–5 min and titrated to patient response

o.), max. 2 mg per dose • ≥20 kg: 2 mg i.v. or i.o.

• Recovery in stage I symptoms

Fentanyl Respiratory depression, somnolence, sleepiness, stupor, coma, amnesia, skeletal

Acetaminophen Stage I (0.5 to 24 h): nausea, vomiting, diaphoresis, pallor, lethargy, malaise or

• Increase in hepatic enzymes (aspartate aminotransferase, alanine

muscle flaccidity, cold and clammy skin, constricted pupils, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring,

aminotransferase) and total bilirubin, PT elongation, oliguria (occasionally)

• Jaundice, hepatic encephalopathy, a marked elevations of hepatic enzymes (exceed 10,000 IU/L) and total bilirubin (above 4.0 mg/dL), hyperammonemia, prolongation of the PT/INR, hypoglycemia, lactic acidosis, death (multiorgan

sweat, constricted pupils, bradycardia, hypotension, QT interval prolongation,

#### **Table 10.**

*Oxycodone and clinically important DDIs [15].*

## **2.4 Fentanyl, acetaminophen, and oxycodone toxicity, clinical manifestations, and management**

The toxicity, teratogenicity (FDA pregnancy category), and carcinogenicity (by the International Agency for Research on Cancer), clinical manifestations, and management of fentanyl, acetaminophen, and oxycodone poisoning are summarized in **Tables 11**–**13**, respectively.


#### **Table 11.**

*Toxicity, teratogenicity, and carcinogenicity of fentanyl, acetaminophen, and oxycodone.*


#### **Table 12.**

**2.4 Fentanyl, acetaminophen, and oxycodone toxicity, clinical manifestations,**

the International Agency for Research on Cancer), clinical manifestations, and management of fentanyl, acetaminophen, and oxycodone poisoning are

**Drugs Fentanyl Acetaminophen Oxycodone** LD50 (mouse, i.p.) (mg/kg) 76 367 320 TDLo (human, oral) (mg/kg) 0.1 490 0.14 FDA pregnancy category C C B Classification by the IARC NA 3 NA

The toxicity, teratogenicity (FDA pregnancy category), and carcinogenicity (by

**and management**

summarized in **Tables 11**–**13**, respectively.

*LD50, median lethal dose; TDLo, lowest toxic dose; NA, not assigned [55–63]*

*Toxicity, teratogenicity, and carcinogenicity of fentanyl, acetaminophen, and oxycodone.*

*Oxycodone and clinically important DDIs [15].*

**Possible effects Clinically important DDI types**

Azelastine, bromperidol, orphenadrine, oxomemazine, paraldehyde, thalidomide

Increase in the CNS depressant effects

*Medical Toxicology*

Enhancement in the serotonergic effects and serotonin syndrome

Urinary retention

**Table 10.**

**Table 11.**

**286**

Enhancement in the bradycardia effects

Enhancement in the psychomotor impairment

**XD C**

Blonanserin, chlormethiazole, CNS depressants, droperidol, flunitrazepam, lemborexant, methotrimeprazine, perampanel, phenobarbital, primidone, sodium oxybate, suvorexant, voriconazole, zolpidem, CYP3A4 inhibitors (strong)

MAOI — Serotonergic agents

— — Anticholinergic agents

— — Succinylcholine

Constipation Eluxadoline — Anticholinergic agents,

— — SSRI

Alizapride, brimonidine,

bromopride, tetrahydrocannabinol, cannabidiol, *Cannabis*, dimethindene, dronabinol, lisuride, lofexidine, magnesium sulfate, metoclopramide, metyrosine, minocycline (systemic), nabilone, piribedil, pramipexole, ropinirole, rotigotine, rufinamide, CYP3A4 inhibitors (moderate)

ramosetron

*Clinical manifestations of fentanyl, acetaminophen, and oxycodone poisoning [16, 61, 64–71].*



Acetaminophen, a non-opioid analgesic, found in hundreds of prescription and OTC medicines, with analgesia and antipyretic effects, often causes hepatotoxicity

overproduction of toxic NAPQI, which occurs during acetaminophen metabolism in the liver, which quickly consumes the glutathione necessary to convert it to the nontoxic metabolite and covalently binds to cell proteins and other vital molecules. Toxicity is more severe in patients with less glucuronidation capacity and/or concomitant use of X- and D-type interacting drugs. The use of activated charcoal within the first 4 h of acetaminophen poisoning and antidote treatment with NAC

After stabilizing the patient, it is necessary to investigate whether poisoning is performed unintentionally or intentionally. If there is substance abuse or suicidal tendency, the patient should be consulted to a psychiatrist, and psychosocial and/or medication for addiction treatment should be started. In unintentional poisonings, adults should be educated/warned by their health protectors about the drugs (effects, duration of action, daily maximum dose, conditions to be considered, side effects, and storage conditions) they use for themselves and/or their children, and additional arrangements should be made to increase the health literacy of the society. If poisoning has developed due to the X- and D-type interactions of the drugs used in therapeutic doses, it should be considered to be subject to periodical/

Department of Medical Pharmacology, Faculty of Medicine, University of Tekirdag

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

(hepatic damage, liver failure) or even death. Toxicity develops due to the

successfully heals liver damage.

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

*Analgesic Poisoning*

continuous training of health protectors.

**Author details**

**289**

Mahluga Jafarova Demirkapu

Namık Kemal, Tekirdag, Turkey

provided the original work is properly cited.

\*Address all correspondence to: mjdemirkapu@nku.edu.tr

**Table 13.**

*Management of acute fentanyl, acetaminophen, and oxycodone toxicity [72–82].*

Antidotal therapy with NAC in acetaminophen poisoning should be applied orally (nonpregnant patients with a functional GI tract and no evidence of hepatotoxicity) or i.v. (patients with vomiting, contraindications to oral administration, and hepatic failure) if:


## **3. Conclusions**

Drugs used in the treatment or prevention of diseases can lead to unintentional or intentional toxicity. Toxicity may be due to high-dose single-drug or multipledrug intake. According to the AAPCC 2018 Annual Report, opioid and non-opioid analgesics often cause single-drug poisoning. The top three of analgesic poisoning are fentanyl, acetaminophen, and oxycodone, respectively.

Opioid analgesics, such as fentanyl and oxycodone, which are preferred in severe pain management, show central and peripheral effects by binding to classical opioid receptors that are widely distributed in the body. Repeated exposure causes an addiction; higher-dose usage to produce the same effect, i.e. tolerance; and withdrawal when stopping intake. Therefore, the dose and severity of toxicity differ between those who take opioid analgesics for the first time and those who are addicted. In poisoning with opioid analgesics, death due to respiratory depression is frequently observed. For this reason, in case of poisoning with opioid analgesics, first of all, adequate ventilation should be provided, subsequent antidote treatment with naloxone should be applied, the patient should be closely monitored for vital functions, and appropriate treatment should be performed when necessary. Since the effect of naloxone is short, application should be repeated when necessary. Supplementary oxygen, endotracheal intubation, and positive end-expiratory pressure should be considered if adequate response cannot be obtained despite a total of 5 to 10 mg of naloxone. Although high doses are not preferred, toxicity is more severe in patients using X and D interactive drugs together.

#### *Analgesic Poisoning DOI: http://dx.doi.org/10.5772/intechopen.92941*

Acetaminophen, a non-opioid analgesic, found in hundreds of prescription and OTC medicines, with analgesia and antipyretic effects, often causes hepatotoxicity (hepatic damage, liver failure) or even death. Toxicity develops due to the overproduction of toxic NAPQI, which occurs during acetaminophen metabolism in the liver, which quickly consumes the glutathione necessary to convert it to the nontoxic metabolite and covalently binds to cell proteins and other vital molecules. Toxicity is more severe in patients with less glucuronidation capacity and/or concomitant use of X- and D-type interacting drugs. The use of activated charcoal within the first 4 h of acetaminophen poisoning and antidote treatment with NAC successfully heals liver damage.

After stabilizing the patient, it is necessary to investigate whether poisoning is performed unintentionally or intentionally. If there is substance abuse or suicidal tendency, the patient should be consulted to a psychiatrist, and psychosocial and/or medication for addiction treatment should be started. In unintentional poisonings, adults should be educated/warned by their health protectors about the drugs (effects, duration of action, daily maximum dose, conditions to be considered, side effects, and storage conditions) they use for themselves and/or their children, and additional arrangements should be made to increase the health literacy of the society. If poisoning has developed due to the X- and D-type interactions of the drugs used in therapeutic doses, it should be considered to be subject to periodical/ continuous training of health protectors.

## **Author details**

Antidotal therapy with NAC in acetaminophen poisoning should be applied orally (nonpregnant patients with a functional GI tract and no evidence of hepatotoxicity) or i.v. (patients with vomiting, contraindications to oral administration,

**Fentanyl Oxycodone Acetaminophen**

For vomiting

• Serum acetaminophen concentration is above the "treatment" line of the

8 h of time of ingestion and acetaminophen ingestion is suspected

• Serum acetaminophen concentration is unavailable or will not return within

• Time of ingestion is unknown and serum acetaminophen level is >10 mcg/mL

• There is evidence of any hepatotoxicity with a history of acetaminophen

• Patient has risk factors for hepatotoxicity, and the serum acetaminophen

Drugs used in the treatment or prevention of diseases can lead to unintentional or intentional toxicity. Toxicity may be due to high-dose single-drug or multipledrug intake. According to the AAPCC 2018 Annual Report, opioid and non-opioid analgesics often cause single-drug poisoning. The top three of analgesic poisoning

Opioid analgesics, such as fentanyl and oxycodone, which are preferred in severe pain management, show central and peripheral effects by binding to classical opioid receptors that are widely distributed in the body. Repeated exposure causes an addiction; higher-dose usage to produce the same effect, i.e. tolerance; and withdrawal when stopping intake. Therefore, the dose and severity of toxicity differ between those who take opioid analgesics for the first time and those who are addicted. In poisoning with opioid analgesics, death due to respiratory depression is frequently observed. For this reason, in case of poisoning with opioid analgesics, first of all, adequate ventilation should be provided, subsequent antidote treatment with naloxone should be applied, the patient should be closely monitored for vital functions, and appropriate treatment should be performed when necessary. Since the effect of naloxone is short, application should be repeated when necessary. Supplementary oxygen, endotracheal intubation, and positive end-expiratory pressure should be considered if adequate response cannot be obtained despite a total of 5 to 10 mg of naloxone. Although high doses are not preferred, toxicity is more

concentration is >10 mcg/mL (66 μmol/L) [80–82]

**Supportive care** For possible coma, seizures, hypotension, and non-cardiogenic pulmonary edema

*Management of acute fentanyl, acetaminophen, and oxycodone toxicity [72–82].*

are fentanyl, acetaminophen, and oxycodone, respectively.

severe in patients using X and D interactive drugs together.

and hepatic failure) if:

**Management steps**

*Medical Toxicology*

**Table 13.**

(66 μmol/L)

ingestion

**3. Conclusions**

**288**

treatment nomogram

Mahluga Jafarova Demirkapu Department of Medical Pharmacology, Faculty of Medicine, University of Tekirdag Namık Kemal, Tekirdag, Turkey

\*Address all correspondence to: mjdemirkapu@nku.edu.tr

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 5
