Pharmacopeia: Acetaminophen

by Lindsay Ripley

Featured art: “Birds in Flight” by John Hughen

Trigger Warning: This piece mentions suicide and drug overdose.

One afternoon, not quite old enough to drive, I sat in the passenger seat of my mom’s Toyota Sienna minivan as she ferried me to the tennis courts where I took lessons and taught drills to younger kids. She focused on the rush hour traffic; I doodled on a homework assignment in my lap. Stopped at a light, she turned to me.

“Sweetie, if you ever try to kill yourself, don’t use Tylenol. It destroys your liver but you’ll probably survive. Kind of the worst that could happen.”

My facial muscles twisted into that expression of disgust and confusion at which teenage girls excel. “Uh, okay, Mom,” I said, then returned to my homework.

She hadn’t spoken so morbidly to me before; I couldn’t imagine what had triggered the thought. Had I unknowingly given some cry for help? Was this her version of such? In retrospect, she’d probably heard something at the office that day about a coworker’s kid attempting suicide and instinctively applied the scenario to her own progeny.

Our brief exchange seemed enough to make my mom happy, having gotten the information she urgently needed to across. Mission accomplished: daughter dropped off for after school extracurricular and taught an important life lesson. Never try to OD on an over-the-counter painkiller. An anxiety had bubbled up in her and was immediately addressed via word vomit about Tylenol. A gastric lavage purging a toxin—one form of treatment.

Most puzzling to me was Mom’s phrasing, which seemed to condone suicide as an act. Even my own. Just so long as the demise took. Years would pass before the idea of suicide even occurred to me, and it’s something I’ve never attempted, at least not actively. Mom had a habit of introducing concepts before I was ready to hear them (In a much earlier memorable car ride she’d asked, “You’re not giving blow jobs, are you?” I had only learned the term a week prior). In both cases, she skipped over potential underlying issues—mood, self-esteem, sexual knowledge, comfort among peers—and went straight to a “problem” that might arise. Why dig in deeper, rooting out the cause, if you can simply vanquish the pain or fever?

I didn’t take Tylenol, generic name acetaminophen (or APAP, both abbreviations of acetyl-para-aminophenol), at that age. I didn’t feel the need for analgesia in a pill until years later when either a sore back from lying in bed binging tv, aching muscles from strenuous workouts, or throbbing hangover headaches would drive me to reach for relief. All these habits rose to a new level during my medical residency. In those years, my drug of choice became Excedrin Migraine—acetaminophen, aspirin, and caffeine.

 * * *

Having completed my medical training, now a general physician in a hospital, I know that acetaminophen is ubiquitous. Finding a pain pill that doesn’t contain Tylenol can be difficult. Acetaminophen mixed with muscle relaxants works wonders for musculoskeletal pain. Tylenol is added to codeine in cough syrups, combined with hydrocodone or oxycodone to make Vicodin and Percocet. Given in the form of a pill, a liquid, a suppository, or intravenously, Tylenol’s methods of administration are virtually limitless. Babies suckle on drops of Tylenol from the tips of syringes.  

In the hospital, acetaminophen is generally preferred to other painkillers given its favorable side effect profile. The kidneys and the stomach lining are safe, unlike with NSAIDs such as ibuprofen. Acetaminophen isn’t physiologically addictive nor does it cause respiratory depression like opiates. As an antipyretic, acetaminophen treats fevers (an earlier version was marketed under the name “Antifebrin”). Perhaps the Superman of drugs—amazing in so many areas, but with one fatal flaw: liver toxicity. Four grams a day is considered maximum dosage in normal substrate. Those with acute liver injury should avoid Tylenol altogether.

Acetaminophen’s precursors were first available for public consumption in the late 19th century. The first was abandoned because it caused problems with hemoglobin’s ability to deliver oxygen to tissues, the second due to issues with kidney failure. Acetaminophen is the third version, taking the mantle from its predecessors in the 1950s. Due to its capacity to destroy an essential organ, some people now wonder if we settled on the wrong version.

 * * *

I stayed in my home state of Texas for college and medical school. But as a liberal in a conservative state, an atheist trapped in religious communities, a country music hater in the land of twang, I wanted out. Less than three months before receiving my doctorate, my fourth-year class and our partners crowded into the gym of the medical school’s fitness center to undergo a process called The Match. Our suits and dresses clashed with the supremely unglamorous venue.

At exactly 9:00 a.m., a faculty member pressed into my hand an envelope shielding an important letter. A letter that would tell me my destination for residency training in internal medicine, the field that deals with those precious internal organs, the liver and kidneys, among several others. And no matter what the underlying medical issue: pain. Always pain.

I slowly tore through the sealed envelope, took out the folded sheet of paper inside, and forced myself to spread it open, revealing my fate: “The University of Washington.” Seattle. A top program in a desirable location. I stared at the name in surprise for a few seconds, double-checked for my name, then turned the text to Will, my live-in boyfriend, waiting anxiously outside my intent focus on the text, to read it. Will didn’t hesitate to accept the result. He smiled, gave me a big hug, then asked “How are you feeling? Are you happy?”

“I guess so. I’m just…surprised.” Truth was, I didn’t know what I felt.

Will and I had been tiptoeing around the subject of marriage. With an upcoming move across the country together, we pulled the trigger that May. A couple weeks later we said our goodbyes to friends and family and drove out west with our belongings, opting to take the more efficient and reliable Volvo XC90 passed down from his dad rather than the covered wagon.

The trip had an ominous start. Only a couple hours west of Dallas, an unsavory smell led to a search through all our things to locate the source. The search ended in the discovery of a months-old, beyond rotten banana in the side pocket of my backpack. I’d carried that backpack with me daily and hadn’t registered the stench. Will insisted I throw out the entire bag. After emptying it of its non-putrid contents, I begrudgingly left my backpack in a dumpster at the side of the road. Things began to look up. We stopped in Berkeley for a few days where Will walked in the official graduation for his doctorate in psychology that he’d completed remotely. Then we turned north, spent a night in Portland where we hit Powell’s books and hiked to a waterfall, and finally arrived triumphantly in Seattle.

Only to find that residency was torture. The excitement of embarking on a new life quickly evaporated. For the first time in my life, something I’d been copiously warned about turned out to be just as difficult as advertised. I withdrew into myself, emotionally shut down. I didn’t have anything left at the end of a long day of sick patients and my raging insecurities at being responsible for them. In the evenings, I’d drink a couple beers, watch the drama of Kim Kardashian and her sisters from my bed (I’d never indulged in reality tv before), pop an Indica gummy (thank you, Washington state), and descend into a fitful sleep.

Summer slipped away quickly. The rain and clouds for which Seattle is notorious dominated most of the year, turning the whole city into shadow. At that high latitude, what sun there was rose late and set early. Our tiny urban apartment that we’d jumped at in a cutthroat housing market sat below ground level—even the scrappiest rays of light that managed to sneak through the clouds at the peak of the day were still blocked by trees and ground, never flooding through our windows.

My new husband and I developed techniques of getting around each other in our dungeon. There, but not there together. In a contained area, but not so restricted that we couldn’t carve out our own spaces. Will, with his freshly minted psychology degree and a budding interest in psychoanalysis, wanted to go deep in processing my feelings. He wanted to have hours-long conversations about my childhood, my hopes, my dreams. I didn’t want to delve into my problems. I wanted to cope in some way that felt comfortable rather than threatening, numb myself to sleep, then pop a few Excedrin Migraine in the morning. I just wanted to survive.

The first year was the hardest. I gained 25 pounds from the beers, trays of donuts at every morning’s teaching conference, and sedentary lifestyle. Sedentary except for my bike rides to and from work. Despite feeling like it sat in a swamp, our apartment rested atop Capitol Hill. A literal hill. While I can’t claim the trip was uphill both ways, my voyage home at the end of the day was invariably an ascent, just not enough to keep off the weight of burden and unhealthy choices.

The stress eased up a bit as I adapted, but each year of residency—and marriage—presented new responsibilities, new challenges. I kept my head down, focused on getting through. Will left town more and more to come home to Texas. He must have liked being gone; I liked when he was gone.

 * * *

Toward the beginning of my second year of residency, I was assigned to do a month of shifts in the emergency department of Harborview, Seattle’s county hospital. The constant shifting between training venues was one thing that made residency so frustrating. As soon as I started to feel comfortable on the cardiology service, at our VA hospital, in my primary care clinic, or a dozen other locations, I’d be ripped out of that setting and plopped down somewhere new. Like starting a new job every month. Don’t let her get too competent or comfortable, I imagined the administrative powers whispering, under the guise of facilitating learning a variety of different things quickly.

I didn’t want to be an emergency department doctor, but the experience was exciting. More akin to what’s depicted on a medical tv show, like the aptly titled “ER,” than the reality of most medical practice. Instead of admitting patients seen by at least one physician already to the hospital, I was on the front lines. I asked the first questions, ordered the first lab tests, initiated the treatment course, decided what level of care the patient needed. Attendings were always around to provide supervision, which quelled some of my anxiety, but I had to seek them out, leaving autonomy relatively intact.

One evening shift in the emergency department, a 19-year-old girl came in with her mother and stepfather. Miranda was chubby, clad in Gossip Girl pajamas, with streaks of blue dye in her otherwise auburn, frazzled hair. I first saw her bouncing in the top of my vision, over the computer I’d laid claim to for a few hours. The triage nurse led her past ten stretchers separated by green curtains, as well as a few beds out in the open where the drunks and heroin overdoses could have eyeballs on them at all times, to an empty bed at the end. Miranda’s parents followed in tow.

She looked so bubbly and innocent—I could imagine a lollipop in her mouth and a teddy bear under her arm. What a contrast to the other patients—homeless people who’d battled life on the streets for years and octogenarian nursing home residents. Harborview dates back to the 19th century, with precious few updates since then to the main structure. The word decrepit comes to mind. That month I shuttled back and forth from the dungeon of my tension-filled apartment to the dungeon of the chaotic and tragic emergency department. Miranda, on the other hand, was young, vibrant. What could possibly be wrong with her?

I was due to add another patient to my load, something I was expected to do at least once an hour, and my curiosity was piqued. So, I pulled up her name on the triage list and scrolled to the chief complaint: APAP ingestion. Oh.

I’d taken care of Tylenol OD’s before, once they were hospitalized, but my only job had been to continue medications already started in the emergency department and trend liver enzymes. Now I’d get to start the treatment, to determine this patient’s path. I might save this girl’s life. Though much of the time I felt overwhelmed, in that moment I felt excited. A discrete medical problem with a clear antidote is not the norm in today’s medical world, dominated by patients with chronic and incurable diseases. I felt powerful. I assigned my name to Miranda and opened up the electronic chart to look over her medical history.

This wasn’t Miranda’s first time at Harborview. And it wasn’t her first time ingesting acetaminophen. In fact, she’d done it about a dozen times, and been seen not only at our hospital, but also multiple others in the area. She demonstrated a clear pattern of behavior: swallow a bottleful of pills in a moment of extreme emotion, then immediately tell someone and be brought docilely to the hospital. Miranda always came straight in. She seemed to know that was important.

 * * *

Acetaminophen is metabolized by three different routes. Normally, all three pathways end in harmless substances that the user urinates out. One particular product of the oxidation pathway, NAPQI, has a potential for toxicity. But NAPQI, too, is quickly conjugated and made harmless by glutathione, an antioxidant that hangs out in the liver like a bodyguard. The problem arises when glutathione is depleted, as with significant acetaminophen use—the bouncers gone, NAPQI builds up and assaults the liver.

Chronic Tylenol use, especially in conjunction with other damaging substances like alcohol, can cause liver damage. Discreet ingestions in large amounts, greater than 10 grams, can lead to acute liver failure and death. Tylenol overdose is the leading cause of acute liver failure in the United States, making acetaminophen the only over-the-counter drug that is reliably fatal.

But we are not powerless in the face of the danger we have created. There is an antidote for acetaminophen ingestion: NAC. Essentially, NAC provides high doses of glutathione, the liver’s protector, allowing NAPQI’s inactivation to continue. If given within the first 8 hours, no matter how much Tylenol was ingested, the chance of hepatic failure or even severe liver damage is extremely rare. But NAC has to be given early. There is a point of no return, where the damage is irreversible, and all we can do is watch the liver fail. My mom was wrong in her original statement—Tylenol, by means of liver failure, will reliably kill you. Just not immediately.

 * * *

I went over to talk to Miranda. She gave permission for her parents to stay in the room (okay, curtained off portion of floor), then answered my questions directly, and I assumed honestly, given the apparent candor.

“When did you take the Tylenol?”

“Almost five hours ago.”

“How much did you take?”

“A whole bottle. Well it wasn’t full. A little over half full, maybe. But it was a big bottle. I had to swallow several handfuls to get it all down.”

“Did you take anything else?”

“No.”

“Why did you take it?”

“I was upset. I had just found out my friend is dating my crush. She’s such a bitch. And my parents wouldn’t give me money to go to this concert that everyone is going to. But after I did it I felt bad about it and I told them.”

“Do you know what happens when you take large amounts of Tylenol?”

“Yeah. You die. That’s why I’m here. I don’t want to die.”

The whole exchange was disturbing. Miranda looked me directly in the eyes, no shame in her admissions. She smiled, giggled, twirled her hair. Her parents were subdued, I assumed from doing this so many times. Miranda seemed physically fine, if mentally off, but I knew enough not to be fooled. In the first 24 hours of acetaminophen poisoning, patients can display nausea, vomiting, diarrhea, malaise, or they can be completely asymptomatic. They appear healthy on the outside. Their liver function tests are totally normal. But if you wait for a display of symptoms, or the liver to show signs of despair, it will be too late to reverse the damage.

I ordered an array of lab tests: basic metabolic panel, complete blood count, liver function tests, pregnancy test. In addition to the standard rainbow, I checked an acetaminophen level, an aspirin level, and a urine toxicology, the latter two to screen for other ingestions Miranda hadn’t admitted to. Trust but verify, goes the medical saying. I put in a consult to the psychiatrists, as Miranda would likely need to go to an inpatient psychiatric unit once she was out of physical danger. All the lab tests came back normal, except the Tylenol level.

There is a tool for deciding if the amount of acetaminophen ingested warrants treatment with NAC. The tool requires you to know how long ago the drug was ingested, and the current amount in the blood. If that amount falls above a line on a graph (the Rumack-Matthew Nomogram), which decreases over time, there is risk for toxicity. Miranda’s number wasn’t off the chart, but it was unequivocally above the line.

So often in the practice of medicine, decisions require integrating multiple types of information and interpreting that through the lens of clinical experience. The kind of stuff with an arduous, painful learning process. I didn’t need any of that here: I had a number, a graph to refer to, and an antidote I knew from medical school. Hence a clear answer, instilling confidence in the course. I took the information I’d gathered, rehearsed the plan I’d formulated, and went to the attending to present the case.

“This is a 19-year-old female with a past medical history of depression, behavioral disorders, and multiple acetaminophen ingestions here with recurrent acetaminophen ingestion. While her labs are currently within normal limits, the timing of her ingestion along with her blood concentration fall above the line to treat, so I am initiating the NAC protocol. I have consulted psychiatry and will call the internal medicine service for admission for continued NAC administration and ongoing monitoring of her liver function.”

I then learned from the attending about the different durations of NAC administration based on when the liver function tests peak and again normalize, and that it can be given orally instead of IV. Usually giving medications orally saves the hospital money. At the attending’s advice, I canceled the order for IV NAC and changed it to oral. Shortly after swallowing the pill, Miranda vomited. I freaked out a bit internally, as the eight-hour mark was looming, and ordered the IV formulation STAT, vowing never to trial the pill instead. And I haven’t.

Though I stayed in the emergency department, I tracked Miranda’s case from afar over the next week. Predictably, her liver function tests, which reflect inflammation in the liver, bumped a bit, then drifted down nicely. She went to inpatient psych for a few days, then back home with her parents, saved to almost certainly do all of this again. In one sense, at least, she was fine.

* * *

There is a saying in residency: the days are long, but the years are short. Time flew by. During that second year I started working out regularly and lost the weight I’d gained despite giving up on biking to and from work, the uphill journey home and the constant rain too much to bear, and depending mainly on public transportation. I made an effort to call my mother back in Texas on my one day off a week. I scheduled trips with friends from medical school on my two weeks off a year.

The routine with my husband continued. The living room was his, the bedroom mine, separated by so much more than a wall. If he couldn’t talk about what he wanted to, he didn’t want to talk at all. He wanted to unearth the rotten banana and throw out everything it had touched. I was too tired and annoyed to look for it. Plus, I needed something to carry my stuff in. There was no large event, but a chronic poisoning of our marriage, that if not addressed would reach a point of no return. Despite seeming focused on health with my ramped-up exercise regimen, I added wine to the beer, plus a splash of Washington cider, and popped more and more Excedrin Migraine for muscle aches and morning hangovers. Occasionally, I wondered how sustainable my strategy of covering up my suffering was. A fleeting musing.

Toward the end of that same year, I rotated through the ICU in our university hospital. Instead of traveling south to get to Harborview, I headed north on my morning commute to the University of Washington campus. Either way I was carried by the inertia of rolling downhill in the morning, whether on my bike, the bus, or tucked in the backseat of an Uber. The quaint trip required passing over a drawbridge, beneath which ran the Montlake Cut where rowers practiced their craft reliably, whether or not the weather was decent. They were built differently, not minding the weather as much as I did. From the big windows of the ICU, I could see the bridge rise and descend, the snow-covered Cascades in the background. I stared out the windows a lot, rather wistfully, though not wistful for things I saw. Wistful for things I couldn’t see.

The rotation itself was grueling—90-hour weeks and deathly ill patients, made worse by the fact that I didn’t have a clearly defined role. What was I supposed to do there? I don’t remember what was going on in my marriage at the time, an indication of where my focus lay; I do remember a handful of cases from that month. Most notably, a woman 30 weeks pregnant died of multi-organ failure from an autoimmune disease. Her baby died with her. I spent that evening on the treadmill, silently crying. I ran harder.

There was also another too familiar acetaminophen ingestion. An 18-year-old boy. His second ingestion. Unlike Miranda, Brandon required the Intensive Care Unit because he’d waited to tell anybody. We started NAC, repleting his glutathione, but not soon enough. Not before signs of liver damage had set in. The castle’s guards showed up to defend their fortress long after the enemy had breached its walls.

The liver has many functions falling into two broad categories: detoxification of harmful substances and synthesis of necessary products. Brandon’s body hoarded bilirubin, a product of the normal breakdown of old red blood cells, causing his skin and eyes to adopt the hue of a highlighter. Ammonia, a byproduct of the body’s use of protein, deposited in his brain, rendering him confused, somnolent, encephalopathic. His INR (bleeding time) crept up, reflecting the lack of clotting factors normally generated by the liver and sitting him up for hemorrhage. Blood oozed around his IV sites and from his gums. Brandon slowly exsanguinated.

There was a minuscule but non-zero chance Brandon’s liver would recover, so when he couldn’t protect his own airway due to worsening obtundation, his parents elected to have him intubated and continue medical support. The nephrologists got involved and initiated dialysis to replace the function of his kidneys, a commonly damaged bystander when the liver fails. Each day it seemed like a new machine had been stuffed into Brandon’s once spacious ICU room. Between the ventilator and dialysis machine, out through the clear glass, I could see a different kind of machine: the boats in the marina. Oh, to be onboard one, sailing away. The deep blue of the water complemented Brandon’s jaundiced skin. He didn’t qualify for a liver transplant because this wasn’t his first overdose. The pattern of behavior he’d demonstrated precluded him.

I happened to be at the adjacent nurses’ station one afternoon when Brandon’s parents came to visit, as they did multiple times each day. When he had been able to, he’d told them to get out. They seemed like nice enough folks, but who knows what had gone on inside their house—more than just the typical teenage angst? He was harder to look at but easier to be around now that he was mostly unconscious. This visit, however, Brandon’s eyes flickered open at the sound of his parents’ voices and he managed to hold up one flimsy middle finger in their direction. He mouthed something around the tube that traveled from the ventilator down into his trachea, which I couldn’t make out, but could only imagine was “fuck you.” He had no trouble expressing his feelings—where did that get him?

I rotated off that service the next day onto god knows where. I remember coming home because when I got off the bus down the street from my apartment complex after dark that night, I realized I didn’t have my keys. The only time that’s ever happened. Fortunately, my husband was home and let me in. He was annoyed at me for refusing to go back to the hospital to see if I’d left my keys in the ICU, which seemed the most likely scenario. I cried when he urged my return, then imbibed a bit and went to sleep. He didn’t understand that I couldn’t go back there.

It turned out the keys had fallen out of my new backpack in the backseat of the Uber I’d taken to work that morning, too late to wait for the bus, which I was able to easily sort out the next day after much-needed rest and distance. I met the Uber driver down the street and gave him $20 for the trouble of returning my keys. Brandon died the day after that, removed from dialysis and the ventilator given no evidence of liver recovery and no other options for survival.

* * *

After residency, Will and I moved back to Dallas. We’d traded up from the hand-me-down Volvo to a brand-new Porsche Macan, who we took on her inaugural road trip. A stop in Twin Falls, Idaho, another in Moab, Utah with a visit to Arches National Park. But no big conversations, our techniques for avoiding each other in a contained space still intact. Despite being surrounded by mountains, Seattle is around sea level. The 2,000-mile journey incurred an elevation gain.

We arrived at our custom-built McMansion funded by Will’s parents, granted physical space we hadn’t had in a while. There weren’t mountains and water, but there was sunlight and warmth. We saw old friends and family. We had let ourselves drift apart, not wanting to rock the boat for me during those unbearable years. Through that, the state of our marriage had reached an impasse. Now something had to be done. One weekend, we decided to drive down to Austin for a music festival, hoping the three-hour trek would allow us to open up, force us to connect, making the road trip once again a catalyst.

It was. Only an hour into the drive we agreed to a divorce. I posed the idea, but it was mutual. That the plan for separation came so easily, out of my own lips, was enough to confirm the marriage was over. Salvaging our relationship had passed the point of no return. Neither of us even cared enough to try.

That same car ride, after my initial sobs receded, we talked over some logistics of how the divorce would work. As we did, entering the northern limits of Austin, a rock flew up from the semi in front of us and chipped the windshield in front of the driver’s seat of my car. Back in Dallas over the next weeks, I moved into the guest room, where I watched Sharp Objects from the bed and fostered a fondness for blueberry vodka. Then I packed and found my own place. Three months after we had moved in, I moved out.

* * * 

I’ve always been careful to limit the amounts of alcohol and post-drinking Tylenol I consume, aware of the dangers to my liver, not overtly wanting to die, and averse to seeking help. My own passive suicidality, variations of which I can identify in most people, tempered by semiconscious risk benefit analyses. I’m nowhere near a Brandon nor a Miranda. I’m a precursor, a different type who does suffer and tries to cope in less than ideal ways, but never progresses to the point of needing medical care. Sticking on a Band-Aid in my own bathroom, putting out fires as they light, treating superficial issues rather than the root of the problem, has been enough to get by.

I wish I could say that I’ve stopped drinking, stopped downing Excedrin Migraine, stopped escaping in reality tv (I’ve moved on to Naked and Afraid), all things benign in small amounts and crippling or fatal in excess, where I fall somewhere in between. But I haven’t. The past four years when driving around, I looked through the chip in the windshield. I never did anything about it, just crossed my fingers and hoped the crack didn’t spread, seeing it at times as a scar of my failures, others as a mark of defiance. A couple months ago another rock flew up, gouging out a new chip. Now too much to tolerate, I had the whole windshield replaced. Clear, unblemished glass to peer through as I drive on.

Lindsay Ripley is an internal medicine physician at a county hospital. She is writing a series of pieces that braid personal and physician memoir and scientific information, each themed on a particular medication.

Jon Hughen is an artist born and raised in Manchester, New Hampshire. They received their BFA in Photography the Institute of Art and Design at New England College. They use their work to collect pieces of their reality and string them together as visual poetry. Jon currently works as part of the Visual Arts Department at Loyola Blakefield Preparatory School teaching Photography and Visual Arts. You can see more of their work at 11-11ArtistStudios.com or on Instagram @jonhughen.