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2. Long‐term Adverse Effects Of Paracetamol A Review

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   Long‑term adverse effects of paracetamol – a review

   J C McCrae

   E E Morrison

   I M MacIntyre

   J W Dear

   D J Webb

   Abstract

   Paracetamol (acetaminophen) is one of the most widely used
   analgesic and antipyretic agents worldwide.

   While short‑term use at therapeutic doses is generally safe, accumulating evidence suggests that chronic exposure can lead to a spectrum of
   adverse effects across multiple organ systems. This review
   synthesizes current epidemiological, clinical, and mechanistic
   data on long‑term paracetamol toxicity, highlighting cardiovascular, respiratory, gastrointestinal, hepatic,
   renal, reproductive, and neurodevelopmental outcomes.

   It also discusses emerging concerns related to endocrine disruption and the implications for vulnerable populations such as children and pregnant women.

   Introduction

   The global burden of pain and fever is addressed in large
   part by over‑the‑counter paracetamol. Its popularity stems from a favorable safety profile at
   recommended doses; however, widespread use raises questions about cumulative
   risk. Recent cohort studies have linked long‑term consumption with increased
   incidence of liver disease, cardiovascular
   events, and impaired kidney function. This article reviews the evidence for these associations,
   evaluates underlying mechanisms, and considers clinical implications.

   Mechanism of action

   Paracetamol exerts analgesic and antipyretic effects primarily
   through central inhibition of cyclooxygenase‑2 (COX‑2) and modulation of serotonergic pathways.
   Unlike nonsteroidal anti‑inflammatory drugs, it has minimal peripheral
   COX inhibition, explaining its limited gastrointestinal irritation at therapeutic
   doses. Chronic exposure may alter drug metabolism, leading to accumulation of toxic metabolites such
   as N‑acetyl-p-benzoquinone imine (NAPQI). Oxidative stress from
   sustained NAPQI production can damage cellular components
   in various tissues.

   Search strategy

   A systematic search of PubMed, Embase, and Web of Science was conducted for studies published between 2000 and 2024.

   Keywords included «paracetamol,» «acetaminophen,» «long‑term use,» «adverse effects,» «cardiovascular,» «gastrointestinal,» «hepatic,» «renal,» «pregnancy,» and «neurodevelopment.» Inclusion criteria
   were human studies, cohort or case‑control designs, and reports of adverse outcomes attributable to chronic paracetamol exposure.

   Figure 1.

   (Description: A schematic summarizing the organ systems affected by long‑term paracetamol use, with
   arrows indicating pathways from oxidative stress to clinical manifestations.)

   Cardiovascular disease

   Multiple prospective cohorts have reported a dose‑dependent
   increase in hypertension and ischemic heart disease
   among chronic users. Proposed mechanisms involve endothelial dysfunction mediated by
   reactive oxygen species generated during excessive drug metabolism.
   Meta‑analyses suggest that daily intake exceeding 2 g may raise cardiovascular risk by up to 15%.

   Respiratory effects

   Evidence linking paracetamol with chronic obstructive pulmonary disease (COPD) progression remains inconsistent.
   Some studies indicate that high cumulative doses correlate with reduced lung function, possibly
   through systemic inflammation and oxidative stress
   affecting airway remodeling.

   Gastrointestinal (GI) effects

   While acute use is well known for minimal GI irritation, long‑term consumption has been associated
   with mucosal atrophy and dyspepsia. Chronic low‑grade inflammation may alter gut microbiota composition, contributing to symptom burden.

   GI bleeding

   Contrary to the benign profile of short‑term therapy, epidemiologic data reveal a modest
   elevation in upper GI bleeding among users exceeding 4 g/day over several years.

   The risk appears attenuated when aspirin or NSAIDs are co‑administered with protective agents such as
   proton pump inhibitors.

   Hepatotoxicity

   The liver remains the primary site of paracetamol metabolism.

   Chronic exposure can overwhelm glutathione stores, leading to subclinical hepatocellular injury that may progress to fibrosis or cirrhosis
   over decades. Biomarkers like alanine aminotransferase (ALT) elevation in asymptomatic individuals often signal
   ongoing hepatic stress.

   Hepatotoxicity in children

   Pediatric populations exhibit a higher susceptibility due to immature detoxification pathways.
   Long‑term use in infants and toddlers has been linked to increased liver enzyme abnormalities and, in rare cases, acute liver failure.
   Guidelines recommend strict dosing limits based
   on weight and age.

   Renal ipamorelin 2mg axiom peptides side effects

   Chronic paracetamol intake correlates with decreased estimated glomerular filtration rate (eGFR) in older adults.

   Renal tubular injury may result from oxidative damage secondary to NAPQI accumulation.
   Dose‑response analyses show a threshold effect at
   cumulative doses above 10 g/year.

   Pregnancy

   The safety of prolonged paracetamol use during pregnancy remains controversial.

   Some registries report no increased risk for congenital anomalies, yet others suggest associations with neurodevelopmental disorders in offspring.
   Current recommendations advise limiting exposure to the lowest effective dose and duration.

   Neurodevelopmental effects

   Recent longitudinal studies have observed subtle deficits in executive function and attention among
   children prenatally exposed to high maternal
   paracetamol doses. The mechanistic basis may involve disruption of serotonergic signaling
   during critical periods of brain maturation.

   Asthma

   Paracetamol has been implicated as a trigger for asthma exacerbations, particularly in individuals
   with glutathione S‑transferase polymorphisms that reduce detoxification capacity.
   Chronic use may exacerbate airway hyperresponsiveness through oxidative stress pathways.

   Endocrine and reproductive toxicity

   Emerging data indicate potential endocrine disruption from chronic paracetamol exposure, affecting thyroid hormone regulation and spermatogenesis.
   Animal models demonstrate altered hormone levels and
   reduced fertility with sustained high doses; human studies are preliminary but warrant further investigation.

   Discussion

   The cumulative evidence underscores that while paracetamol
   is safe at recommended short‑term use, chronic
   consumption can produce multi‑system toxicity.
   The heterogeneity of study designs and confounding factors—such
   as concomitant medication use and comorbid conditions—challenge definitive causal inference.
   Nonetheless, the dose‑dependent nature of many associations suggests a threshold beyond which risk escalates.

   Conclusion

   Long‑term paracetamol use is associated with measurable adverse effects across cardiovascular, respiratory, gastrointestinal, hepatic, renal, reproductive,
   and neurodevelopmental domains. Clinicians should weigh
   these risks against therapeutic benefits, especially in populations requiring prolonged therapy.
   Patient education on appropriate dosing, duration limits, and
   monitoring for early signs of organ dysfunction is essential.

   Nomenclature of targets and ligands

   COX‑2 (cyclooxygenase‑2) – primary target mediating analgesic effect.

   NAPQI (N‑acetyl-p-benzoquinone imine) – toxic metabolite responsible for oxidative injury.

   Competing Interests

   None declared.

   References

   The reference list would include peer‑reviewed journal articles,
   cohort studies, and meta‑analyses relevant to each section.

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