EPSA Science! Monthly: The Science of Intoxication

Introduction

Dear readers,

Did you know that any substance has the potential to be toxic? Even our favourite beverage, water, can also be poisonous! In fact, the dose is, among other factors, responsible for making the poison.

In this edition, students from NAPSer will take you on a journey to the science of intoxication. In the first part of this journey, you will find some stories about poisons used in the old times. You will learn how ancient folks used to deploy toxins in revenge and to achieve their different goals.

Afterwards, you will read about the epidemiology of intoxication and toxidromes. Then you will dive into the depth of the science of poisoning with our beloved painkiller, Paracetamol, and with Tricyclic antidepressants! Pay attention to this part and prepare yourself to solve some clinical cases in the end.

Enjoy reading!

Rahaf Alsayyed

About NAPSer

The National Association of Pharmacy Students - Serbia (NAPSer) is a student organisation made up of all students of pharmacy and pharmacy medical biochemistry in Serbia. NAPSer has five local offices, founded at the Faculties of Pharmacy or Medicine in Belgrade, Novi Sad, Kragujevac and Niš. When enrolling in pharmacy studies, every student becomes a member of student organisations and realises professional and personal improvement opportunities. Through various educations, soft skills training and competitions, as well as student exchanges and foreign internships, and European and World congresses, NAPSer offers students the opportunity to expand their knowledge, improve their communication skills, get to know other cultures, and also to make good memories and friends for all life.

Authors

Vanja Petrić, 4th year of study, Faculty of Pharmacy; Belgrade, Serbia

Đorđe Stanivuk, graduate student Faculty of Pharmacy; Belgrade, Serbia

Aleksandra Savić, graduate student, Faculty of Medicine Niš, Department of Pharmacy; Niš, Serbia

The history of poisoning1

Poisoning occupies a significant chapter in human history, as it was one of the principal killing weapons used in ancient times, mainly because people had difficulties differentiating poisoning and disease symptoms. Poisoning has been found in crime scenes, wars, and personal revenge scenarios. The knowledge of poisonous agents is also as old as humanity. Paracelsus (1492 1541), a Swiss physician and chemist who lived in the renaissance, studied toxicology and is best known for his postulate that says: “the dose makes the poison”, which means that any substance can be toxic1 .

For example, water and alcohol are both toxic at some point. Excessive water consumption, for instance, in people with some mental disorders, can lead to toxicity, but the median lethal dose (LD50) for water is approximately 6L. Meanwhile, LD50 of alcohol is roughly 585 mL of 40% alcohol by volume2

Some poisoning examples from history are found below:

Curare is a poison used in prehistory. Back then, people used to add it to the tips of their arrows to hunt animals. That used to guarantee an immediate death of the prey. Curare is isolated from Strychnos toxifera (Loganiaceae).

Later on, people started using poisons to kill each other, not only for hunting purposes. For example, many substances were used in ancient Greece to kill people. The most remarkable example is the death of Socrates, the Greek philosopher (470 399 BC). He was castigated by making him drink the extract of hemlock (Conium maculatum, Apiaceae). Also, the death of Alexander the Great (356 323 BC). They say that he was poisoned to death by his wife, who, according to stories, used strychnine to kill him. Strychnine is a poisonous alkaloid extracted from Strychnos nux-vomica (Loganiaceae). Nowadays, strychnine is used as a raticide and is sometimes found mixed with street drugs. It is a competitive inhibitor of the glycine receptor in the spinal cords. Given that the glycine receptor is an inhibitor receptor, strychnine causes severe muscle spasms, which can lead to the spasm of breathing muscles and death3

In the middle age, Catherine de Medici (1519 1589), the so called Queen Poisoner, used poisons to achieve her political ends. She also used to test toxic substances in the lower class. In other words, Catherine de ’Medici used to perform highly unethical experiments aiming to study toxins.

Aqua Tofana4

At the end of the 17th century, many Italian women used to look for ways to escape their bad marriages, and one of the ways to do so was by poisoning their husbands and inheriting their husbands’ fortunes. It was estimated that more than 600 husbands were poisoned with Aqua Tofana back then.

Aqua Tofana, also called Acqua Toffana, Acquetta Perugina, Aqua Tufania, or Manna di San Nicola) was a potent poison invented in Sicily around 1630.5 This poison is associated with Giulia Tofana, or Tofania, a woman from Palermo and a leader of a six poisoners gang in Rome. This poison was first mentioned in 1632 1633 when two women used it to kill their victims.

The active ingredients of Aqua Tofana are not entirely known but seemed to be based on arsenic, antimony, lead, and possibly corrosive sublimate (mercury (II) chloride) and belladonna. The method of mixing them is not known.

Aqua Tofana was colourless, tasteless, and liquid. Therefore, it was easily mixed with water or wine and served during meals. Owing to those properties, poisoning with Aqua Tofana could go unnoticed. Also, it acts slowly, with symptoms resembling those of progressive diseases or other natural causes. As the main ingredient is arsenic, the observed intoxication symptoms are similar to arsenic poisoning. It is believed that Mozart's death was due to this poison. In addition, only 5 6 drops of this Aqua Tofana were sufficient to kill a man, and death was highly controllable, as it was possible to determine when the person would die.

The reported symptoms of intoxication are throat pain, stomach pain and vomiting, thirst and diarrhoea. The antidote for this poison was lemon juice and vinegar. Under the trade name “Manna of St Nicholas of Bari”, the strong poison could be conveniently stored in an average woman’s makeup container, making it easy and accessible for anyone5 .

Mechanism of arsenic poisoning

Because of arsenate and phosphate structural similarity, arsenate can replace phosphate in several metabolic pathways. This leads to its interaction with various metabolites with which phosphate normally reacts, disrupting glucose homeostasis and the formation of adenosine triphosphate (ATP), the primary source of cellular energy6 .

In oxidation state III, Arsenic has a high affinity for sulfur atoms, creating stable conjugates with thiols. Such binding can inhibit or completely prevent the action of

those enzymes which contain thiol and potentially disrupt the entire metabolic pathways. One of the most important enzymes inhibited this way is the pyruvate dehydrogenase complex6,7 .

To manage arsenic intoxication, normally chelating agents are administered. The most recommended ones are 2-3-dimercapto-1-propane sulfonate (DMPS) or meso2,3 dimercaptosuccinic acid (DMSA) due to their water solubility. They show low toxicity compared to previously used antidotes8

Epidemiology of intoxication and Toxidromes

Intoxication is an important daily faced health issue. It happens either deliberately or coincidentally. Imagine yourself walking in a forest where charming mushrooms look delicious. You are courageous enough to pick them up and prepare a good meal. You may end up hospitalised because this meal turns out TOXIC! If you are still alive, be cautious next time!

Causes and consequences of intoxication differ between countries and age groups. Studies found that in developing countries such as European and North American ones, child poisoning is accidental. On the other hand, adult poisoning is deliberate in most cases. Insects and snake bites are the most predominant cause of children's poisoning, and some household products and medicines are also behind children's poisoning. However, for adult poisoning, analgesics are the most predominant cause9 . In developing countries, pesticide poisoning was found to be the leading cause of intoxication, and it was either intentional or accidental.9

It is estimated that each year, from 2015 to 2019, 140,000 people died from excessive alcohol drinking in the USA.10 Also, in the USA, there were 91,799 deaths caused by drug overdose in 2020, and the main responsible drugs were found to be opioids, accounting for 74.8% of all those cases.11

Many foods contain naturally occurring poisons and toxins. Bitter almonds, for example, contain traces of cyanide that prevent cells in our bodies from using oxygen and, therefore, from surviving.12 Cyanide is also naturally present in many other plants used as food, including apples, peaches, apricots, lima beans, barley, sorghum, flaxseed, and bamboo shoots.13 Studies show that 0.5 to 3.5 mg/kg of body weight can be lethal14. Cyanide can also exist as a gas. The most common source of cyanide poisoning is fire, which turns its inhalation highly toxic. Data shows that 3165 people were exposed to cyanide from 1993 to 2002 and that 2.5% were fatal15 .

Toxidrome16

Toxidrome is a syndrome caused by dangerous levels of toxins in the body17 The signs and symptoms of a toxidrome often reflect the effect of the toxic agent on neuroreceptors. It occurs in response to a drug overdose, and common signs and symptoms depend on the insulting agent. For example, one can find increased heart rate, delirium, dry mouth, mydriasis, and dry skin in the case of anticholinergic toxidrome. On the other hand, sympathomimetic toxidrome is characterised by increased heart rate and blood pressure, agitation, delirium, mydriasis, and excessive sweating.

Opioids and sedative-hypnotic agents’ toxidrome are described by decreased respiratory rate and/or shallow breath, as well as a decrease in consciousness and miosis only in the case of opioids.

Cholinergic agents’ toxidrome is the opposite of anticholinergics and is identified by decreased heart rate, diaphoresis, lacrimation, miosis, salivation, and urination. In addition, bronchoconstriction and bronchorrhea cases can happen, which are lethal. More examples of toxidromes are discussed ahead.

Paracetamol

Paracetamol (Acetaminophen) is an analgesic and antipyretic drug. Its clinical use started in 1893. This drug is over the counter (OTC) in many countries, which means it is available for most of the population18

Paracetamol poisoning was first described in the 1960s. It is provoked by the excessive use of this medicine. Most people have few or non specific symptoms in the first 24 hours following an overdose. Those symptoms are described as abdominal pain, nausea, vomiting, and anorexia. Then, they are typically followed by a couple of days without any symptoms, followed by some biochemical alterations, after which yellowish skin, blood clotting problems, and confusion result from liver failure. Additional complications may include renal failure, pancreatitis, hypoglycemia, and lactic acidosis. If the overdose did not lead to death, people tend to fully recover over two weeks19 .

In 2009, paracetamol overdose was considered the first leading cause of acute liver failure in the USA, with 26000 hospitalised cases and more than 450 annual deaths. Furthermore, paracetamol intoxication is regarded as the leading cause of acute liver failure in the USA and the UK. Further studies revealed that this overdose was deliberate in 27 44% of cases and unintentional in 48% to 61% of cases19

Mechanism of intoxication When taken in therapeutic doses (maximum 4000 mg/day in adults, and 10 15 mg/kg of body weight maximum five times/day in children)18, paracetamol is safe. The toxic dose of paracetamol is highly variable, but the lowest amount to cause hepatotoxicity is between 125 150 mg/Kg of body weight20

Like many other drugs, paracetamol, at normal doses, is metabolised and eliminated from the body. Its metabolism takes place by phase I and phase II enzymes. Phase II enzymes conjugate a part of paracetamol to glucuronate and sulfate, rendering it non-toxic and eliminable19. Phase I enzymes. Namely, CYP450 2E1 are oxidising enzymes and lead to the formation of reactive intermediate N acetyl p benzoquinone imine (NAPQI), a compound responsible for hepatotoxicity at high doses of paracetamol. At normal doses, NAPQI is detoxified by reacting with reduced Glutathione (GSH). However, after an overdose of paracetamol, there is no more GSH available for detoxification, as all available GSH is conjugated to NAPQI21 . Consequently, NAPQI, the toxic metabolite, reacts with the cellular membranes of hepatocytes leading to their damage and, later on, to hepatic necrosis19 .

Some people are more prone to this toxicity, and risk factors include alcoholism, malnutrition, comedication with other hepatotoxic medications, history, serum levels of paracetamol, and possible other etiologies of hepatic dysfunction.22

Diagnosis is based on the blood level of paracetamol at specific times after ingestion. These values are often plotted on the Rumack Matthew nomogram, which estimates the risk of toxicity based on the serum concentration of paracetamol at given hours after intake. Paracetamol level is traced along the nomogram to determine potential hepatotoxicity risk Using a timed serum paracetamol level plotted on the nomogram appears to be the best23 .

Paracetamol can be quantified in plasma or urine as a diagnostic tool in clinical poisoning situations or in the case of a medicolegal investigation of suspicious deaths. After death, blood levels range between 50 and 400 mg/L in persons dying from acute overdosage24. Automated colourimetric techniques, gas chromatography and liquid chromatography are currently in use for the laboratory analysis of the drug in physiological specimens25 .

Tricyclic antidepressants (TCA)

Tricyclic antidepressants (TCA) are a drug class that was first released to the market in 1959 as a pharmacotherapy for major depressive disorder (MDD)26

However, they are no longer used as the first line therapy for MDD due to many safety concerns. TCA has some unpleasant adverse effects compared to other antidepressant classes, such as Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Noradrenaline Reuptake inhibitors (SNRIs). So, they are only used in people suffering from severe cases of depression and in those who do not respond to other classes of antidepressants.

TCA can also be used to manage other mental conditions, for instance, in obsessive compulsive disorder (OCD) and bipolar disorder. Amitriptyline, clomipramine, dosulepin, imipramine, lofepramine and nortriptyline are the most common TCAs. Highlighting amitriptyline for its application in managing nerve pain.27

The off label uses of TCAs include migraine prophylaxis, OCD, insomnia, anxiety, and chronic pain, especially neuropathic pain conditions such as myofascial pain, diabetic neuropathy, and postherpetic neuralgia. Regarding migraine prophylaxis, doxepin and amitriptyline are found to be used more frequently. In addition, TCAs are also the second line treatment for fibromyalgia after pregabalin, duloxetine, or milnacipran.26

Toxicity and Treatment of overdose

Tricyclic antidepressants (TCAs) generally have a narrow therapeutic index and, therefore, are prone to induce toxicity if an intentional overdose occurs. They were shown to have higher death rates per one million prescriptions than other antidepressants. This is due to higher rates of suicide by deliberate overdose.28

Older TCAs, such as desipramine, nortriptyline, and trimipramine, have been shown to induce toxicity at lower doses than newer TCAs, such as amitriptyline. Overdose signs include electrocardiogram (ECG) abnormalities such as QT interval prolongation and widened QRS complex, hypotension, seizures, tremors, coma, xerostomia, urinary retention, and respiratory depression29 .

The leading cause of death due to TCA overdose is hypotension and arrhythmias. To treat overdose, activated charcoal can be used to prevent drug absorption; this must be given within two hours of the drug ingestion30

Mechanisms of toxicity31

TCAs mechanism of action lies in central inhibiting serotonin and noradrenaline reuptake. So, exaggerated inhibition in overdose conditions can lead to seizures. Toxic levels of TCAs lead to the blockage of the following receptors:

1. muscarinic receptors, leading to anticholinergic toxidrome that is characterised by tachycardia, fever, dry mouth and skin, and unconsciousness

2. histaminic receptors, leading to altered mental status

3. alpha adrenergic in the periphery, leading to hypotension

Toxicity management31

Respiratory depression is a common manifestation of TCA intoxication, so respiratory intervention is indispensable, typically by intubation. Hypotension is managed by IV fluids and sodium recuperation due to the blockage of peripheral alpha adrenergic and cardiac toxicity. Noradrenaline injection is used as a second line if no response is noticed

Activated charcoal is often administered orally within 2 hours of ingestion to clean the GI tract.

Seizures are managed with benzodiazepines and sometimes with anticonvulsant agents.

Sodium bicarbonate is given to narrow QRS and adjusts serum pH between 7.5 7.55. This molecule increases blood pH and, therefore, decreases the active form of the medication as TCA need an acidic environment for the formation of the ionised form and the potentiation of their effects.

Temporary pacemakers can be used to treat refractory bradycardias not responding to sodium bicarbonate. Lidocaine and phenytoin are antiarrhythmic agents and can be used as adjunctive therapy in overdose treatment.

TCA should not be used concomitantly with monoamine oxidase inhibitors (MAOI) due to the risk of developing serotonin syndrome. Patients with serotonin syndrome present with dilated pupils, hyperreflexia, myoclonus, diarrhoea, tremors, and confusion. The treatment of serotonin syndrome includes cooling, discontinuation of serotonergic drugs, and the administration of cyproheptadine32 .

Clinical Cases

Clinical case 133:

A.K, female, 23 years old, low Body Mass Index (BMI), with malnutrition. She arrives at the hospital emergency with the following signs and symptoms: Drowsiness, confusion, and fluctuating consciousness. Opiate toxicity was excluded.

Blood tests:

● pH 7.22, pCO2 3.9 kPa, base excess (BE) 11 mmol/L and lactate 7.9 mmol/L

● Creatinine 52 µmol/L

● Alanine aminotransferase (ALT) 562 U/L, alkaline phosphatase 122 U/L and bilirubin 12 µmol/L

● International Normalised Ratio (INR) 0.99

● The plasma ammonia level was 72 µmol/L

● Plasma paracetamol level was 536 mg/L

After a conversation with her family, doctors found that she has a history of depression and other mental disorders. She took 47.5 g paracetamol (864 mg/kg body weight) as well as codeine and ibuprofen. She also consumed alcohol 24 hours before hospitalisation.

Questions:

a) According to this clinical scenario, what is behind this clinical situation?

b) What is the most suitable treatment?

Answers:

a) Signs and symptoms of downness, confusion and fluctuating consciousness suggest intoxication.

According to the blood test, this patient has lactic acidosis and abnormal liver function, but the synthetic liver function is good, yet. According to paracetamol levels in the blood > 500 mg/L, developing acute liver failure is very likely. From the creatinine level, one can notice that renal function is normal, and blood tests suggest intoxication with paracetamol.

b) The traditional treatment is delivering N acetylcysteine (NAC) as it provides cysteine for GSH synthesis and therefore removes the toxic metabolite of paracetamol (NAPQI). However, in this case, NAC alone cannot resolve the problem, as the maximum tolerated dose of NAC is 300 mg/Kg and remember that the patient has ingested 864 mg/kg of paracetamol, then NAC is not

enough (reaction stoichiometry 1:1). Therefore, the patient was transferred to hemodialysis section to remove blood acidity and clean the blood from the paracetamol, maintaining on NAC and fluid resuscitation.

Clinical case 234: G.H, female, approximately 55 years old, arrives at the hospital’s emergency late at night. Before arriving at the hospital, she started seizing, so doctors administered intranasal midazolam.

a) Explain the administration of intranasal midazolam.

To stop the seizure

Paramedics informed that she was found unconscious in her house, next to an empty bottle of amitriptyline. A family member stated that she has a history of chronic pain syndrome.

b) What is the possible cause of unconsciousness, in your opinion?

TCA toxidrome, more specifically, intoxication with amitriptyline due to an intentional overdose.

She was immediately intubated to protect her airways. She arrives at the emergency 45 minutes after amitriptyline ingestion. After diagnosis, her vital signs were found the following:

● Blood pressure: 47/36

● Bradycardia (registered ECG)

c) What do you conclude from her vital signs?

That she has hypotension and cardiotoxicity

d) One hour after arriving at the emergency room, she was injected with two ampules of sodium bicarbonate and 1mg of atropine. Why?

To overcome hypotension and bradycardia, IV fluids and atropine were administered. Atropine was used due to its anticholinergic properties; therefore, it is considered an acceptable option for managing bradycardia. Despite those measures, she was still hypotensive, so sodium bicarbonate was administered. After this, improvements in cardiotoxicity were noticed.

e) Would activated charcoal administration be helpful in this case?

Yes, because she was hospitalised after 45 min of amitriptyline ingestion, which is less than 2 hours after the ingestion, so the activated charcoal was still effective.

f) Later she was transferred to the intensive care unit (ICU) in a stable yet critical condition, there norepinephrine was administered. Why?

To treat refractory hypotension

Also, continuous propofol drip and lorazepam were given to maintain sedation. She was also admitted to a psychiatric facility to treat her major depressive disorder. She was sent back home with no neurological or cardiac “sequelae” with a follow up.

References:

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2. The Dose Makes the Poison. (n.d.). ChemicalSafetyFacts. Retrieved 19 August 2022 from https://www.chemicalsafetyfacts.org/dose-makes-poison-gallery/

3. Facts About Strychnine. (2018, April 4). CDC. Retrieved 23 August 2022 https://emergency.cdc.gov/agent/strychnine/basics/facts.asp#:~:text=People%20e xposed%20to%20high%20doses,Brain%20death

4. Dash, M. (2017). Aqua Tofana. In Toxicology in the Middle Ages and Renaissance (pp. 63 69). Elsevier. https://doi.org/10.1016/B978 0 12 809554 6.00006 8

5. Hannah McKennett. (2022, June 1). Meet Giulia Tofana: The 17th Century Professional Poisoner Said To Have Killed 600 Men. https://allthatsinteresting.com/giulia tofana

6. Sattar, A., Xie, S., Hafeez, M. A., Wang, X., Hussain, H. I., Iqbal, Z., Pan, Y., Iqbal, M., Shabbir, M. A., & Yuan, Z. (2016). Metabolism and toxicity of arsenicals in mammals. Environmental Toxicology and Pharmacology, 48, 214 224. https://doi.org/10.1016/j.etap.2016.10.020

7. Hughes, M. F. (2002). Arsenic toxicity and potential mechanisms of action. Toxicology Letters, 133(1), 1 16. https://doi.org/10.1016/S0378 4274(02)00084 X

8. How Should Patients Overexposed to Arsenic Be Treated and Managed? (2010, Spring). ATSDR. Retrieved 19 August 2022 from https://www.atsdr.cdc.gov/csem/arsenic/patient_exposed.html

9. Meredith, T. J. (1993). EPIDEMIOLOGY OF POISONING. 59(3), 251 256. https://doi.org/10.1016/0163 7258(93)90069 P

10. Alcohol and Public Health. (n.d.). CDC. Retrieved 19 August 2022, from https://www.cdc.gov/alcohol/features/excessive alcohol deaths.html

11. Drug overdose. (n.d.). CDC. Retrieved 19 August 2022 C.E., from https://www.cdc.gov/drugoverdose/deaths/index.html

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12. Facts About Cyanide. (n.d.). CDC. Retrieved 19 August 2022, from https://emergency.cdc.gov/agent/cyanide/basics/facts.asp

13. Diana Lutz. (2010, July 20). Beware the smell of bitter almonds. Why do many food plants contain cyanide? THE SOURCE. https://source.wustl.edu/2010/07/beware the smell of bitter almonds/

14. Apricot kernels pose risk of cyanide poisoning. (n.d.). Efsa. Retrieved 19 August 2022, from https://www.efsa.europa.eu/en/press/news/160427

15. Graham J, Traylor J. (2022). Cyanide Toxicity. StatPearls Publishing.

16. Weier, A., & Kleinschmidt, K. (2010). How Are Patients Who Are Admitted to the Intensive Care Unit after Common Poisonings Diagnosed and Managed? In Evidence Based Practice of Critical Care (pp. 632 636). Elsevier. https://doi.org/10.1016/B978 1 4160 5476 4.00090 0

17. Guidotti, T. L. (2015). Hydrogen sulfide intoxication. In Handbook of Clinical Neurology (Vol. 131, pp. 111–133). Elsevier. https://doi.org/10.1016/B978-0-44462627 1.00008 1

18. Paracetamol (Acetaminophen). (n.d.). NIH National Library of Medicine.

21 August 2022, from https://www.ncbi.nlm.nih.gov/books/NBK526213/

19. Chun, L. J., Tong, M. J., Busuttil, R. W., & Hiatt, J. R. (2009). Acetaminophen

and Acute Liver Failure. Journal of Clinical Gastroenterology, 43(4),

349. https://doi.org/10.1097/MCG.0b013e31818a3854

20. Zachary Brennan. (2015, November 16). FDA Amends Liver Warning Labeling Guidance for Some OTC Drugs Containing Acetaminophen. Regulatory Focus.

focus%E2%84%A2/news articles/2015/11/fda amends liver warning labeling guidance for some otc drugs containing acetaminophen#:~:text=The%20US%20Food%20and%20Drug,mg%20of%20acet

21. Zhao, L., & Pickering, G. (2011). Paracetamol metabolism and related genetic differences. Drug Metabolism Reviews, 43(1), 41–52. https://doi.org/10.3109/03602532.2010.527984

22. Rumack, B. H., & Matthew, H. (1975). Acetaminophen Poisoning and Toxicity. Paediatrics, 55(6), 871 876. https://doi.org/10.1542/peds.55.6.871

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23. Fisher, E. S., & Curry, S. C. (2019). Evaluation and treatment of acetaminophen toxicity. Advances in Pharmacology (Vol. 85, pp. 263 272). Elsevier. https://doi.org/10.1016/bs.apha.2018.12.004

24. Randall C. Baselt. (1944). Disposition of Toxic Drugs and Chemicals in Man (12th ed., Vol. 1 44). https://doi.org/10.1093/jat/bkaa121

25. Bose, D., Durgbanshi, A., Martinavarro Dominguez, A., Capella Peiro, M. E., Carda Broch, S., Esteve Romero, J. S., & Gil Agusti, M. T. (2005). Rapid Determination of Acetaminophen in Physiological Fluids by Liquid Chromatography Using SDS Mobile Phase and ED Detection. Journal of Chromatographic Science, 43(6), 313 318. https://doi.org/10.1093/chromsci/43.6.313

26. Jordan Moraczewski; Kapil K. Aedma. (2022, May 2). Tricyclic Antidepressants. NIH National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK557791/

27. Overview—Antidepressants. (2021, November 4). NHC. https://www.nhs.uk/mental health/talking therapies medicine treatments/medicines-and-psychiatry/antidepressants/overview/

28. Henry, D. J. A. (1989). A fatal toxicity index for antidepressant poisoning. Acta Psychiatrica Scandinavica, 80(S354), 37 45. https://doi.org/10.1111/j.1600 0447.1989.tb03045.x

29. I R Starkey, A A Lawson. (1980). Poisoning with tricyclic and related antidepressants A ten year review. 49(193), 33 49. https://pubmed.ncbi.nlm.nih.gov/6776584/

30. Pentel, P. R., & Benowitz, N. L. (2012). Tricyclic Antidepressant Poisoning. 1, 21.

31. Muhammad M. Khalid; Muhammad Waseem. (2022, July 18). Tricyclic Antidepressant Toxicity. NIH National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK430931/

32. Schipper, P., & Vanmolkot, L. (2016). Combineren van klassieke monoamine oxidaseremmer en tricyclisch anti depressivum bij therapieresistente depressie: Gevalsbeschrijving en literatuuroverzicht. TIJDSCHRIFT VOOR PSYCHIATRIE, 5.

33. Serjeant, L., Evans, J., Sampaziotis, F., & Petchey, W. G. (2017). Haemodialysis in acute paracetamol poisoning. BMJ Case Reports, bcr2016218667. https://doi.org/10.1136/bcr 2016 218667

EPSA European Pharmaceutical Students’ Association

34. Clark, S., Catt, J. W., & Caffery, T. (2015). Rapid diagnosis and treatment of severe tricyclic antidepressant toxicity. BMJ Case Reports, bcr2015211428. https://doi.org/10.1136/bcr-2015-211428

References of infographics:

Infographic 1: Aqua Tofana Dash, M. (2017). Aqua Tofana. In Toxicology in the Middle Ages and Renaissance (pp. 63 69). Elsevier. https://doi.org/10.1016/B978 0 12 809554 6.00006 8

Infographic 2: Intoxications Drug overdose. (n.d.). CDC. Retrieved 19 August 2022 C.E., from https://www.cdc.gov/drugoverdose/deaths/index.html

Facts About Cyanide. (n.d.). CDC. Retrieved 19 August 2022, from https://emergency.cdc.gov/agent/cyanide/basics/facts.asp

Weier, A., & Kleinschmidt, K. (2010). How Are Patients Who Are Admitted to the Intensive Care Unit after Common Poisonings Diagnosed and Managed? In Evidence Based Practice of Critical Care (pp. 632 636). Elsevier. https://doi.org/10.1016/B978 1 4160 5476 4.00090 0

Infographic 3: Paracetamol overdose Paracetamol (Acetaminophen). (n.d.). NIH National Library of Medicine. Retrieved 21 August 2022, from https://www.ncbi.nlm.nih.gov/books/NBK526213/

Chun, L. J., Tong, M. J., Busuttil, R. W., & Hiatt, J. R. (2009). Acetaminophen Hepatotoxicity and Acute Liver Failure. Journal of Clinical Gastroenterology, 43(4), 342 349. https://doi.org/10.1097/MCG.0b013e31818a3854

Infographic 4: Tricyclic antidepressants Jordan Moraczewski; Kapil K. Aedma. (2022, May 2). Tricyclic Antidepressants. NIH National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK557791/ Muhammad M. Khalid; Muhammad Waseem. (2022, July 18). Tricyclic Antidepressant Toxicity. NIH National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK430931/

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