Acetaminophen

Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. However, acetaminophen is believed to exert its effects through indirect and reversible inhibition of cyclooxygenase (COX)-1 and COX-2. The effects are generally limited to the CNS. Acetaminophen is primarily metabolized by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver; therefore, an overdose can lead to life-threatening hepatotoxicity. In adults, limiting the total acetaminophen dose (from all sources and routes) to < 4000 mg/day is highly recommended. Contraindications to acetaminophen use include hypersensitivity, severe hepatic impairment, or severe active hepatic disease.

Last update:

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Chemistry and Pharmacodynamics

Definition

Acetaminophen, also known as paracetamol (N-acetyl-p-aminophenol), is a nonopioid analgesic and antipyretic agent used to treat pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever.

Chemical structure

  • Derivative of p-aminophenol
  • Chemical formula: C8H9NO2
Acetaminophen (n-acetyl-p-aminophenol)

Acetaminophen (N-acetyl-p-aminophenol)

Image: “Acetaminophen (N-acetyl-p-aminophenol)” by Huang. License: CC BY 3.0

Mechanism of action

  • The exact mechanism of action is not fully understood.
  • The effects are believed to be via the indirect inhibition of cyclooxygenase (COX)-1 and COX-2 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in the CNS (by central COX inhibition).
  • Weak inhibitor of COX in the peripheral tissues

Physiologic effects

  • Prostaglandins (PGs) play a key role in acute inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation.
  • The cardinal signs of inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation are observed:
    • Rubor (redness)
    • Calor (heat)
    • Dolor ( pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain)
    • Tumor (swelling)
  • PG production is dependent on COX-1 and COX-2.
  • Indirect inhibition of COX → ↓ PG synthesis → ↓ inflammatory response

Pharmacokinetics

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

  • Oral:
    • High bioavailability (88%)
    • Onset of action < 1 hour
    • Peak concentration attained after 90 minutes
  • Rectal:
    • Bioavailability approximately 50%
    • Onset of action < 1 hour
    • Peak concentration not reached until 3 hours
  • IV:
    • Bioavailability up to 100%
    • Onset of action < 10 minutes
    • Peak concentration attained in about 60 minutes

Distribution

  • Even distribution throughout most tissues and fluids except in fat
  • Crosses the blood-brain barrier and placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity; found in breast milk
  • Low plasma protein binding (25%)

Metabolism

  • Metabolized primarily by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and follows 1st-order kinetics:
    • Conjugation with glucuronide
    • Conjugation with sulfate
    • Oxidation via the cytochrome P450 (CYP) pathway (primarily CYP2E1)
  • Metabolism via the CYP2E1 pathway results in the production of N-acetyl-p-benzoquinone imine (NAPQI).
  • NAPQI is a toxic metabolite:
    • Rapidly conjugated with glutathione
    • Detoxified by glutathione → nontoxic cysteine and mercaptate compounds → renal excretion
  • Note: Drugs administered orally are subject to 1st-pass metabolism.

Excretion

  • Metabolites are primarily excreted in the urine:
    • Majority as glucuronide metabolites, then as sulfate metabolites
    • < 10% as metabolites of cysteine and mercapturic acid

Indications

Acetaminophen is an equivalent of aspirin and has analgesic and antipyretic effects; however, acetaminophen does not have platelet-inhibiting effects nor does it affect uric acid levels.

Fever

  • Temporary reduction of fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Can be used in individuals of all ages

Pain

  • Oral/rectal: temporary relief from minor aches, pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and headaches
  • IV: 
    • Relief from mild-to-moderate pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Relief from moderate-to-severe pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain when combined with an opioid
    • Should only be used in individuals ≥ 2 years of age

Adverse Effects and Contraindications

Adverse effects of oral/rectal acetaminophen

  • Hepatic (most significant): 
    • Associated with doses > 4000 mg/day and the use of > 1 acetaminophen-containing product (can lead to acetaminophen overdose Acetaminophen Overdose Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose)
    • Limit total dose from all sources and routes to < 4000 mg/day (adults).
    • Manifestations:
      • Increased liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
      • Acute hepatic failure
      • Hepatotoxicity
  • Other effects:
    • Otic: hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
    • Dermatologic: erythema, rash, Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome, toxic epidermal necrolysis
    • Hypersensitivity: hypersensitivity reactions, anaphylaxis

Adverse effects of IV acetaminophen

  • Hepatic (most significant):
    • Increased ALT and AST levels
    • Acute hepatic failure
    • Hepatotoxicity
  • GI (> 10%): nausea, vomiting, constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • ≤ 10%:
    • Cardiovascular: hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension or hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema (adults)
    • Dermatologic: rash, Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome, toxic epidermal necrolysis
    • Endocrine and metabolic: hypoalbuminemia, hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, hypomagnesemia, hypophosphatemia
    • Genitourinary: oliguria
    • Hematologic: anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Hypersensitivity: hypersensitivity reaction, anaphylaxis
    • Local: pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain at infusion site
    • Nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System: agitation, headache, insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia, trismus
    • Musculoskeletal: muscle spasms
    • Respiratory: dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, stridor, wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing, pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion, pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema

Drug-drug interactions

Table: Drug-drug interactions
Drugs Interactions/effects
Alcohol (ethyl) ↑ Hepatotoxicity
Barbiturates
  • ↑ Metabolism of acetaminophen
  • ↓ Therapeutic effect of acetaminophen
  • ↑ Risk of hepatotoxicity
Carbamazepine
  • ↑ Metabolism of acetaminophen
  • ↓ Therapeutic effect of acetaminophen
  • ↑ Risk of hepatotoxicity
Fosphenytoin-phenytoin
  • ↓ Serum concentration of acetaminophen
  • ↑ N-acetyl-p-benzoquinone imine formation
Isoniazid ↑ Hepatotoxicity
Lamotrigine ↓ Serum concentration of lamotrigine
Local anesthetics Local anesthetics Local anesthetics are a group of pharmacological agents that reversibly block the conduction of impulses in electrically excitable tissues. Local anesthetics are used in clinical practice to induce a state of local or regional anesthesia by blocking sodium channels and inhibiting the conduction of painful stimuli via afferent nerves. Local Anesthetics ↑ Risk of methemoglobinemia Methemoglobinemia Methemoglobinemia is a condition characterized by elevated levels of methemoglobin in the blood. Methemoglobin is the oxidized form of hemoglobin, where the heme iron has been converted from the usual ferrous (Fe2+) to the ferric (Fe3+) form. The Fe3+ form of iron cannot bind O2, and, thus, leads to tissue hypoxia. Methemoglobinemia
Prilocaine ↑ Likelihood of methemoglobinemia Methemoglobinemia Methemoglobinemia is a condition characterized by elevated levels of methemoglobin in the blood. Methemoglobin is the oxidized form of hemoglobin, where the heme iron has been converted from the usual ferrous (Fe2+) to the ferric (Fe3+) form. The Fe3+ form of iron cannot bind O2, and, thus, leads to tissue hypoxia. Methemoglobinemia
Rifampin ↑ Hepatotoxicity of acetaminophen

Contraindications

  • Hypersensitivity to acetaminophen or any components of the IV formulation
  • Severe impairment of liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver function or active hepatic disease

Comparison of Medications

Table: Comparison of acetaminophen and NSAIDs
Drug class Acetaminophen NSAIDs
Mechanism of action Indirect inhibition of COX Inhibition of COX
Physiologic effect Decreased inflammatory response Decreased inflammatory response
Indications
  • Pain
  • Fever
  • Inflammatory diseases
  • Rheumatoid disorders
  • Pain
  • Fever
  • Dysmenorrhea
  • Osteoarthritis Osteoarthritis Osteoarthritis (OA) is the most common form of arthritis, and is due to cartilage destruction and changes of the subchondral bone. The risk of developing this disorder increases with age, obesity, and repetitive joint use or trauma. Patients develop gradual joint pain, stiffness lasting < 30 minutes, and decreased range of motion. Osteoarthritis
Contraindications
  • Anaphylaxis
  • Hypersensitivity
  • Severe hepatic impairment
  • Severe active hepatic disease
  • Anaphylaxis
  • Hypersensitivity
  • Aspirin- or NSAID NSAID Nonsteroidal antiinflammatory drugs (NSAIDs) are a class of medications consisting of aspirin, reversible NSAIDs, and selective NSAIDs. NSAIDs are used as antiplatelet, analgesic, antipyretic, and antiinflammatory agents. Nonsteroidal Antiinflammatory Drugs-induced asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma or urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives)
  • Renal impairment (CrCl < 30)
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care after 20-weeks gestation
  • Use in the setting of CABG
COX: cyclooxygenase
CrCl: creatinine clearance
CABG: coronary artery bypass graft

References

  1. Burns, M.J., Friedman, S.L., Larson, A.M. (2021). Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation. UpToDate. Retrieved July 14, 2021, from https://www.uptodate.com/contents/acetaminophen-paracetamol-poisoning-in-adults-pathophysiology-presentation-and-evaluation
  2. Candido, K.D., Perozo, O.J., Knezevic, N.N. (2017). Pharmacology of acetaminophen, Nonsteroidal antiinflammatory drugs, and steroid medications: Implications for anesthesia or unique associated risks. Anesthesiol Clin 35, e145–e162.
  3. Forrest, J.A.H., Clements, J.A., Prescott, L.F. (1982). Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet 7, 93–107.
  4. Gerriets, V., Anderson, J., Nappe, T.M. (2021) Acetaminophen. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482369/
  5. Ghanem, C.I., Pérez, M.J., Manautou, J.E., Mottino, A.D. (2016). Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity. Pharmacol Res 109, 119–131.
  6. Ghlichloo, I., Gerriets, V. (2021). Nonsteroidal anti-inflammatory drugs (NSAIDs). StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK547742/
  7. Grosser, T., Smyth, E., FitzGerald, G. (2017). Pharmacotherapy of inflammation, fever, pain, and gout. Brunton, L.L., Hilal-Dandan, R., Knollmann B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=170271972
  8. Heard, K., Dart, R. (2021). Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents. UpToDate. Retrieved July 14, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-acetaminophen-paracetamol-poisoning-in-children-and-adolescents
  9. Mazaleuskaya, L.L., et al. (2015). PharmGKB summary: Pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genom 25, 416–426.
  10. Raffa, R.B., et al. (2015). Pharmacokinetics of oral and intravenous paracetamol (acetaminophen) when co-administered with intravenous morphine in healthy adult subjects. Clin Drug Invest 38, 259–268.
  11. Ricciotti, E., FitzGerald, G.A. (2011). Prostaglandins and inflammation. Arteriosclerosis Thrombosis Vasc Biology 31, 986–1000.
  12. Shagroni, T.T., Cazares, A., Kim, J.A., Furst, D.E. (2021). Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, nonopioid analgesics, & drugs used in gout. Katzung, B.G., Vanderah, T.W. (Eds.), Basic & Clinical Pharmacology, 15e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250600111
  13. Solomon, D.H., Furst, D.E., Romain, P.L. (2020). NSAIDs: Therapeutic use and variability of response in adults. UpToDate. Retrieved July 14, 2021, from https://www.uptodate.com/contents/nsaids-therapeutic-use-and-variability-of-response-in-adults

USMLE™ is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). MCAT is a registered trademark of the Association of American Medical Colleges (AAMC). NCLEX®, NCLEX-RN®, and NCLEX-PN® are registered trademarks of the National Council of State Boards of Nursing, Inc (NCSBN®). None of the trademark holders are endorsed by nor affiliated with Lecturio.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

User Reviews

0.0

()

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details