Medication overdoses and toxicities: Pathology review

A 19 year old young man named Cameron is brought to the emergency room by his father, who found Cameron vomiting next to a half-empty bottle of aspirin. Cameron tells you that he has a headache and is hearing a weird ringing noise. You decide to perform a blood test, which reveals that Cameron has metabolic acidosis.

Later that day, 32 year old Adaline presents in the emergency room due to nausea, vomiting, and slurred speech. Adaline reports that she has the flu and has been taking ibuprofen for the last couple of days. You notice that Adaline is very thirsty, and she also keeps going to the restroom to urinate. Her history reveals that she was diagnosed with bipolar disorder a few years ago, and is currently under treatment with lithium.

Based on their history and presentation, both Cameron and Adaline seem to have some type of medication overdose or toxicity. An overdose refers to taking too much of a substance, and can result in toxicity, which refers to how harmful that substance can be to the body.

Now, let’s go over some pharmacology basics. The therapeutic index, or TI for short, is a quantitative measurement of a drug’s dosing and its safety. For your exams, you should know that the TI is calculated as the ratio of the median toxic dose or TD50, which is the dose that causes a toxic response in 50% of the population, over the median effective dose or ED50, which is the dose that causes a therapeutic effect in 50% of the population.

Now, if the test question gives you a median lethal dose or LD50 for short instead of TD50, don’t panic! These two can be used interchangeably in the formula, but keep in mind that TD50 refers to human clinical trials, while LD50 refers to animal studies, and is defined as the dose that causes death in 50% of tested animals.

The important thing to note here is that medications with a wide therapeutic index are safer, since their toxic dose is much higher than their effective dose. On the flip side, medications with a narrow therapeutic index are more dangerous, since they have close toxic and effective doses.

Now, in contrast to the therapeutic index, there is the therapeutic window, which is defined as the range of blood concentrations at which a medication can give therapeutic effects while avoiding toxicity. The therapeutic window refers to any blood concentration of a given drug that’s between two parameters. The first one is minimum effective concentration or MEC, which refers to the minimum concentration that has therapeutic effects. The other one is minimum toxic concentration or MTC, which refers to the minimum concentration that has toxic effects. Everything between these two concentrations represents the therapeutic window.

Okay, for your tests, some frequently tested medication overdoses and toxicities include anticholinergic medications, acetaminophen, salicylates, tricyclic antidepressants, lithium, beta blockers, digoxin, warfarin, and heparin.

First, let’s start with anticholinergic toxicity, which is mainly associated with anticholinergic medications such as atropine and scopolamine; but also antihistamines, such as loratadine, as well as tricyclic antidepressants or TCAs, such as amitriptyline. Now, what anticholinergics do is they block the cholinergic receptors, which normally get activated when they bind to the neurotransmitter acetylcholine in the peripheral and central nervous system.

Now, the most common symptoms in individuals with anticholinergic toxicity include flushed skin, dry skin and mucous membranes, and anhidrosis or decreased sweating. In addition, anticholinergics can affect the eyes, causing blurry vision, mydriasis or dilated pupils; and cycloplegia or paralysis of the ciliary muscle of the eye, which impairs eye accommodation. Other high yield clinical features include hyperthermia or increased body temperature, tachycardia or increased heart rate, constipation, and urinary retention; as well as mental symptoms, such as disorientation, confusion, hallucinations, and delirium.

For your exams, here’s a memory trick to recall the main symptoms of anticholinergic toxicity: red as a beet for flushed skin, dry as a bone for anhidrosis, hot as a hare for hyperthermia, blind as a bat for mydriasis and cycloplegia, mad as a hatter for mental symptoms like hallucinations and delirium, and finally full as a flask for urinary retention.

Finally, some less common but still high yield symptoms of anticholinergic toxicity include myoclonus, meaning brief involuntary muscle twitching or jerky contractions, as well as choreoathetosis, which is a combination of chorea or involuntary and irregular spasmodic movements and athetosis or involuntary writhing movements.

Now, for treatment of anticholinergic toxicity, you must absolutely remember that the antidote is physostigmine, which is an acetylcholinesterase inhibitor. Now, acetylcholinesterases are enzymes that normally break down acetylcholine. So by inactivating them, physostigmine increases the concentration of acetylcholine, which counteracts the anticholinergic effects. For your exam, it’s important to know that physostigmine is a tertiary amine, therefore it can cross the blood brain barrier and act on the central nervous system.

Next is acetaminophen, also known as paracetamol, which is an over the counter medication that’s commonly used to treat pain and fever. Now, acetaminophen works by reversibly inhibiting the COX enzymes in the central nervous system, thereby decreasing production of prostaglandins that cause pain and fever. It’s important to note that in the periphery, prostaglandins also mediate inflammation; however, acetaminophen doesn't inhibit the COX enzymes peripherally, so it doesn't have anti-inflammatory effects.

For your exams, remember that acetaminophen is metabolized by the hepatocytes in the liver and then excreted via the kidneys. Most of it is metabolized by glucuronidation and sulfation into non-toxic metabolites, which are then excreted via urine. However, a small amount of acetaminophen is metabolized via oxidation by the enzyme cytochrome P450 or CYP450 into a highly toxic metabolite called N-acetyl-p-benzoquinone imine or NAPQI for short. This toxic metabolite is normally inactivated by an antioxidant called glutathione; so at therapeutic doses, acetaminophen doesn’t usually cause severe side effects.

On the other hand, with acetaminophen overdose, the hepatocytes can’t break down all the acetaminophen by glucuronidation and sulfation, so the remaining acetaminophen undergoes CYP450 oxidation, which creates more NAPQI. Keep in mind though that there’s a limited amount of glutathione in hepatocytes, so eventually glutathione is depleted. As a consequence, there’s build up of NAPQI, which leads to liver injury and hepatocyte death.

It’s important to note that this can also occur with therapeutic doses of acetaminophen in individuals with low glutathione stores, such as infants, elderly, individuals with malnutrition, or with a genetic condition called glutathione synthetase deficiency, where individuals don’t have enough of the enzyme glutathione synthetase that helps produce glutathione.

On the other hand, some individuals may have enhanced CYP450 activity due to chronic use of alcohol, or some medications like barbiturates, phenytoin, and carbamazepine; causing NAPQI production to ramp up.

Early symptoms of acetaminophen toxicity include nausea, vomiting, and abdominal pain. As the liver injury progresses, individuals may develop late symptoms associated with acute hepatic necrosis and liver failure. This can present with jaundice or yellowing of the skin, coagulopathy or impaired clot formation, and hepatic encephalopathy or brain dysfunction that’s due to liver disease. In addition, excessive amounts of acetaminophen and NAPQI can be nephrotoxic and cause acute renal failure.

Treatment of acetaminophen toxicity involves administration of N-acetylcysteine, which replenishes glutathione, as well as activated charcoal, which binds to acetaminophen and prevents its absorption in the gastrointestinal tract.

Next, we have salicylates, such as aspirin, which are non-steroidal anti-inflammatory drugs or NSAIDs. Unlike acetaminophen, salicylates work by irreversibly inhibiting the COX enzymes both centrally and peripherally, thereby reducing pain and fever, but also inflammation, and can inhibit platelet aggregation.

When there’s salicylate overdose, early symptoms can include vomiting, tinnitus or ringing in the ears, and nausea. In addition, higher salicylate doses may directly stimulate the respiratory center, leading to hyperventilation, or very rapid and deep breathing. Hyperventilation can then lead to respiratory alkalosis, which is when there’s a blood pH that’s higher than 7.45, while the partial pressure of carbon dioxide is below 35 millimeters of mercury.

Over time, individuals may start developing late symptoms of salicylate overdose, such as a headache and fever. In addition, salicylates may start to disrupt oxidative phosphorylation and fatty acid beta oxidation, which generate ATP via aerobic metabolism. As a result, the body switches to anaerobic metabolism, which produces lactic acid. As lactic acid builds up, individuals develop metabolic acidosis, which is when blood pH goes below 7.35, while bicarbonate concentration is less than 22 milliequivalents per liter. Now, keep in mind that salicylate is an ionized or charged particle, but in conditions of acidosis, salicylate shifts towards its unionized form called salicylic acid. What’s important is that salicylic acid can easily cross the blood brain barrier and cause agitation, delirium, seizures, and coma. If not treated on time, salicylate overdose can be fatal.

There's no specific antidote for salicylate overdose, so treatment includes administration of activated charcoal, which binds to aspirin and prevents its gastrointestinal absorption; as well as sodium bicarbonate for alkalization of urine, which facilitates salicylate excretion.

On a related note, another high yield condition associated with aspirin is Reye syndrome, which is a rare but life-threatening condition characterized by hepatic encephalopathy that develops in some children that take aspirin to treat a viral infection, especially influenza and varicella. For that reason, it’s very important to avoid giving aspirin to children. The only exception to this rule is the use of aspirin in children with Kawasaki disease, which is an acute febrile disease of unknown cause that’s characterized by vasculitis or an inflammation of the blood vessels.

Normally, aspirin is metabolized by the liver, and its metabolites are excreted through the kidneys. What’s important here is that Reye syndrome develops when aspirin metabolites reversibly inhibit mitochondrial enzymes in the hepatocytes, and subsequently disrupt oxidative phosphorylation and fatty acid beta oxidation. As a result, fatty acids build up in the liver, leading to steatosis or fatty liver.

For your exams, remember that a liver biopsy would show mitochondrial abnormalities and microvesicular accumulation of fat in hepatocytes. In addition, hepatocytes are unable to produce enough ATP and start to die off. Ultimately, the liver becomes dysfunctional and is unable to convert glycogen to glucose, leading to hypoglycemia or low blood sugar. In addition, the dysfunctional liver is unable to clean the blood from toxic substances like ammonia. As a result, this ammonia is free to diffuse across the blood brain barrier and interfere with brain function, causing encephalopathy. And unfortunately, many children with Reye syndrome decline within a few days to coma and death. Treatment of Reye syndrome usually involves careful in-hospital monitoring and supportive care.

Switching gears, tricyclic antidepressants, or TCAs for short, are medications that are mainly used to treat major depressive disorder. Now, TCAs have a narrow therapeutic index and window, which makes them one of the common causes of fatal medication overdose. To help you remember the most dangerous symptoms of TCA overdose, think of the 3 C’s for tri- Cy- Cli- Cs. The first C is for convulsions or seizures. The second C is for cardiotoxicity, which can manifest as a prolongation of QT interval and arrhythmias. And the third C is for coma, which is often associated with severe respiratory depression. And another pretty characteristic manifestation is hyperpyrexia or body temperature that exceeds 41°C or 106°F.

Treatment of TCA overdose mainly consists of supportive care, as well as activated charcoal to avoid gastrointestinal absorption of TCAs. In addition, individuals can be given sodium bicarbonate in order to prevent arrhythmias, together with continuous ECG monitoring.

All right, now moving on to lithium, which is a medication that’s mainly used for psychiatric conditions like bipolar disorder. Now, you must absolutely remember that lithium has a narrow therapeutic index and window, therefore small variations in its blood concentrations can have serious effects. In fact, the most common causes of lithium toxicity include increased lithium dosage; decreased renal elimination, which is common in individuals with acute kidney injury; and the use of medications that can affect renal clearance, such as ACE inhibitors, thiazide diuretics, and NSAIDs.

For your exams, the most important manifestations of lithium toxicity include nausea, vomiting, and slurred speech. In addition, individuals may develop seizures, hyperreflexia or overactive reflexes, and ataxia, which refers to a lack of coordination and muscle control. Finally, lithium therapy is the most common cause of nephrogenic diabetes insipidus, which is characterized by polyuria, or the production of large quantities of very dilute urine, as well as polydipsia or extreme thirst.